The neuroscience of cancer: Focus on neuropeptidergic systems

The neuroscience of cancer: Focus on neuropeptidergic systems

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Zikai Dong^a^,^b, Yongfei Wang^a^,^b, Weilin Jin^a^,^b^,^*

Acta Pharmaceutica Sinica B | 2025, 15(5) : 2323 - 2350

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Acta Pharmaceutica Sinica B | 2025, 15(5): 2323-2350

• REVIEW •

The neuroscience of cancer: Focus on neuropeptidergic systems

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Zikai Dong^a^,^b, Yongfei Wang^a^,^b, Weilin Jin^a^,^b^,^*

Affiliations

^aInstitute of Cancer Neuroscience, Medical Frontier Innovation Research Center, the First Hospital of Lanzhou University, the First Clinical Medical College of Lanzhou University, Lanzhou 730000, China

^bThe First Clinical Medical College of Lanzhou University, Lanzhou 730000, China

About Author:

E-mail address: ldyy_jinwl@lzu.edu.cn (Weilin Jin).

Author contributions

Zikai Dong: Writing – original draft, Visualization, Conceptualization. Yongfei Wang: Writing – original draft. Weilin Jin: Writing – review & editing, Supervision, Funding acquisition, Conceptualization.

doi: 10.1016/j.apsb.2025.03.025

Outline

Abstract

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Tumors are complex, highly heterogeneous diseases that place an enormous burden on the world's healthcare systems. Updating understanding of tumor initiation and progression is critical and the current breakthrough lies in cancer neuroscience, which focuses on the crosstalk between neural components and tumors. Neuropeptides are a class of highly potent peptides, that perform the physiological functions of neurotransmitters, neuromodulators, and endocrine hormones. Currently, many studies have shown that many cellular components of the tumor microenvironment express neuropeptides and their receptors and that neuropeptides may play an important role in their cellular communication. In addition, neuropeptides and their receptors affect cancer hallmarks such as proliferation, invasion and metastasis, angiogenesis, immune escape, metabolic reprogramming, and others. More importantly, neuropeptides may also affect some tumor comorbidities such as insomnia, depression, anorexia, cancer pain, and others. Targeting neuropeptides in combination with new therapeutic strategies may significantly advance anti-tumor therapy, not only for treating the tumor itself but also for improving the patient's quality of life.

Key words

Cancer neuroscience / Drug repurposing / Comorbidity / GPCRs / Neuropeptides / Targeted therapy / Tumor microenvironment / Tumor macroenvironment

Cite this Article

Zikai Dong, Yongfei Wang, Weilin Jin. The neuroscience of cancer: Focus on neuropeptidergic systems[J]. Acta Pharmaceutica Sinica B, 2025 , 15 (5) : 2323 -2350 . DOI: 10.1016/j.apsb.2025.03.025

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1.　Introduction

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Cancer remains intractable due to its complex pathogenesis and highly plastic progression, which places a significant economic and social burden¹. Researchers make plenty of effort to handle this dilemma. One of the advances has been updating knowledge about tumor development and progression: we are becoming aware that the nervous system significantly impacts tumors². High intratumoral nerve density correlates with worse outcomes in some solid tumors such as prostate cancer, head and neck cancer, pancreatic cancer, and breast cancer^3—6. The crosstalk between cancer and nerves, termed cancer neuroscience, attracts researchers. Recently, Borniger⁷ summarized corresponding fields comprehensively and proposed an innovative mode of their interaction. It is believed that the nervous system plays an important role in the sensation of tumors and the integration of cancer-related signals. Finally, the nervous system reciprocally influences systemic physiology relevant to cancer. Tumors, as homeostatic challenges, also affect and even reshape the nervous system. This process is based on the action of signaling molecules. For example, tumors could secrete several cellular factors such as nerve growth, brain-derived neurotrophic factors, glial cell-derived neurotrophic factors, and several guidance molecules to promote axonogenesis and innervation^8—11. In turn, intratumoral nerves could release neurotransmitters, neuropeptides, neural hormones, and other substances to promote cancer progression. Researchers have now had some success in understanding the effects of neurotransmitters on tumors¹². As for neuropeptides, due to their sheer number and complexity, they still need to be deeply studied.

Sufficient evidence exists to show that peptidergic innervation exists in tumors. For example, Neuropeptide Y (NPY)-immunoreactive nerves can be observed in colorectal cancer, renal cell carcinomas, nephroblastoma, and adrenal cortical tumors^13—15. Tumors also express neuropeptide receptors on their surface or even secrete neuropeptides in an autocrine means. Accumulating evidence supports that activation of neuropeptide receptors can significantly affect cancer behavior. They participate in tumor proliferation, immunoregulation, invasion, metastasis, and angiogenesis, and somehow influence cancer-related microbiomes, via paracrine, autocrine, and endocrine means, which is context-dependent¹⁶. The complicated functions they play in tumor development have troubled researchers to a great extent. How to understand the paradoxical role of neuropeptides is likewise a challenge. In that case, in the so-called tumor macroenvironment, neuropeptides may play a broader role as signaling molecules, influencing the progression of the tumor disease alone and participating in the development of tumor comorbidities. Solid evidence supports that the dyshomeostasis of neuropeptides leads to the aberrant situation of the whole body, resulting from the significant roles of neuropeptides in the homeostatic regulation of physiological functions.

Considering the important role of neuropeptide signaling, targeting the neuropeptide system may be one of the important manners of tumor therapy. An interesting direction could be the repurposing of these compounds to target neuropeptide receptors. It has been shown that aprepitant, an antagonist of the neurokinin-1 receptor (NK1R), significantly hinders tumor development¹⁷. In this review, we provide a detailed summary of how peptidergic nerves communicate with tumors and the sophisticated mechanisms by which neuropeptides regulate cancer progression and cancer comorbidities. We also present some discussion on the therapeutic promise of neuropeptides and their receptors, especially their importance in targeted therapies.

2.　Characteristics of neuropeptides and their receptor

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We can term a molecule a neuropeptide when it fulfills the following characteristics: (1) It's a small peptide molecule. (2) It's produced and secreted by neurons or works on neurons. (3) It plays a role in the regulation of the nervous system, serving as neurotransmitters or hormones¹⁸. According to traditional beliefs, neuropeptides are the class of signaling molecules like the classical neurotransmitters to mediate the communication among neurons, glial cells, and peripheral cells¹⁹. But compared with the classic ones, neuropeptides could long-lastingly mediate neural processing. As concepts have evolved, many peptides are not synthesized by neurons that are also classified as neuropeptides because they could also regulate activities of the central nervous system. In a later section, we will briefly describe the synthesis, secretion, classification, and function of neuropeptides, as well as some other features, especially those that significantly differ from neurotransmitters.

2.1.　 Synthesis, secretion, and deactivation

Typically, neuropeptides range in size from about 3 to 100 amino acids, and about 75% of neuropeptides are no larger than 30 amino acids. Unlike monoamine neurotransmitters which are mainly derived from multiple chemical modifications of amines, the synthesis of neuropeptides travels a longer travel. The synthesis is generally divided into two steps: precursor peptide synthesis and mature peptide modification. Precursor peptides undergo a series of processes in the endoplasmic reticulum, including shearing, phosphorylation, acetylation, and sulphation to produce mature peptides. A case in point is proopiomelanocortin (POMC)-derived peptide. POMC, a precursor polypeptide, carries the amino acid sequences of many small polypeptides, such as adrenocorticotropic hormone, endogenous opioid β-endorphin, and melanocyte-stimulating hormone (MSH)^20,21. The capacity of POMC to synthesize a multitude of neuropeptides or hormones is a consequence of the actions of various enzymes, such as pro-hormone convertase 1/2/3, and carboxypeptidase E²².

Neuropeptides are stored in large dense-core vesicles (LDVs) in nerve endings, in contrast with classical neurotransmitters stored in small synaptic vesicles. However, most of the neurons contain both two vesicles. This phenomenon is called the co-existence of neuropeptides and small-molecule neurotransmitters which was first observed by Vincent et al²³. The existence of this condition lies in the diversity of rich neurotransmitter regulation. Compared with small synaptic vesicles, LDVs will only be released at higher firing rates. So, when a presynaptic neuron is firing at a low frequency, only the neurotransmitter will be released. While it's overexcited, both neuropeptides and neurotransmitters will be secreted into the synaptic cleft and subsequently bind to their receptors on postsynaptic neurons. In this situation, neuropeptides could regulate the drastic effect made by neurotransmitters.

The mechanism of deactivation also differs between the classic neurotransmitters and neuropeptides. Neurotransmitters such as norepinephrine (NE) and dopamine (DA), are deactivated by specific enzymes and by reuptake into the presynaptic terminal. As for neuropeptides, presynaptic neurons rarely reuptake them, and they are frequently degraded by specific peptidase enzymes.

2.2.　 Classification of neuropeptides and receptors

To date, there are nearly 2500 kinds of vertebrate neuropeptides recorded by various databases²⁴. Due to the large number of neuropeptides, it is difficult to classify them into different families using an individual taxonomic approach. Currently, neuropeptides are categorized into small or large families based on genetic similarity, molecular similarity, functional similarity, or homology to the site of production²⁵. According to Hökfelt et al.²⁶, some of the long-length established families so far include the hypothalamic hormones, hypothalamic releasing and inhibiting hormones, tachykinins family, opioid peptides family, NPY and related peptides family, VIP-glucagon family, and others. The current categorization is tedious and cumbersome, and it is worth considering whether there is a more sensible means.

In general, neuropeptides bind to their corresponding receptors to exert their functions, most of which are G-protein coupled receptors (GPCRs). Based on structural and functional characteristics, the large number of GPCRs can be roughly grouped into the following families: class A, class B, class C, and class F²⁷. Class A GPCRs, also termed the rhodopsin-like family, are the most abundant and studied superfamily²⁸. Opioid receptors, somatostatin receptors, galanin receptors, bombesin receptors, and others all belong to the class A family. Class B GPCRs can be further subdivided into secretin (B1), with a large extracellular structural domain, and adhesive (B2), with a unique long N-terminal motif and an autoproteolytic-inducing structural domain²⁹. Class B family contains fewer receptors than class A, including vasoactive intestinal peptide (VIP) receptors, calcitonin receptors, and the other eleven receptors. As for the class C family, the glutamate family consists of γ-aminobutyric acid B receptors, calcium-sensing receptors, metabotropic glutamate receptors, sweet and amino acid taste receptors, and serval orphan receptors³⁰. Class C family has some unique features distinguished from others. First, despite the universal structure of GPCRs, the class C family has an extracellular domain that comprises a Venus flytrap module and a cysteine-rich domain³¹. The large extracellular domain contains the orthostatic binding site for ligands, while in the 7TM region, only allosteric binding sites are found. The fact that they function only as homodimers or heterodimers is another unique feature of the class C family³¹. To date, there are no known neuropeptide receptors that belong to this family. Class F GPCRs are composed of 10 frizzled receptors and one smoothened receptor, distinguished by shared CRD regions and engagement in the Wnt and Hedgehog signaling pathways³². Of course, there are no neuropeptide receptors belonging to this family. As the research progressed, a new family of GPCRs, class F, was identified, consisting mainly of taste 2 receptors. It was isolated because its sequence similarity to the existing family was less than 20%²⁷.

Despite the large number of GPCRs and the complexity of their classification, they share a similar core structure: seven transmembrane α-helices that weave in and out of the membrane. Upon binding to corresponding ligands, the GPCR exposes intracellular sites that interact with the G protein heterotrimer containing the α, β, and γ subunits³³. It catalyzes the detachment of GDP attached to the Gα subunit and its displacement by GTP, thus causing the dissociation of Gα from the Gβγ subunit. The Gα and Gβγ subunits complex subsequently stimulate several downstream effectors and finally lead to signaling cascades. It's believed that neuropeptides and their counter GPCRs are involved in various biological activities in both normal physiological and pathological conditions.

2.3.　 Signaling pathways of neuropeptide receptors

Neuropeptides not only serve as neurotransmitters but also hormones, exerting plenty of functions such as cell survival, proliferation, secretion, and motility. These functions are based on complex signal transduction mediated by neuropeptide receptor activation (Fig. 1).

Serval neuropeptide receptors are coupled to the Gα_q subunit, leading to the activation of phospholipase C, which mainly sociates calcium elevation and protein kinase C (PKC) activation. PKC subsequently promotes phosphorylation of serine/threonine proteins³⁴.

A greater number of neuropeptide receptors are coupled to Gα_s subunit, whose activation subsequently stimulates adenylyl cyclase (AC) synthesis of cyclic adenosine monophosphate (cAMP). The transitory cAMP flux could regulate numerous cellular processes via two major downstream machinery: protein kinase A (PKA) and guanine nucleotide exchange protein activated by adenylyl cyclase (EPAC)^35,36. PKA, a tetrameric enzyme, could phosphorylate the serine and threonine in substrates³⁷. For example, PKA could phosphorylate calmodulin-dependent protein kinase kinase-2 (CAMKK2) and subsequently inactivate it, whose functions mainly link to energy hemostasis³⁸. The more important function of PKA is to phosphorylate transcription factors such as the cAMP response element binding protein/activating transcription factor (CREB/ATF) family. Activated CREB and ATF1 could attach to the cAMP response element (CRE) present in the promoter region of target genes and trigger transcription³⁹.

cAMP could also bind to the cAMP-nucleotide binding-B domain (CNBD-B) on EPAC and lead to a conformational shift releasing the autoinhibition and exposing Cdc25-HD for the RasF-like guanine triphosphatase (Rap). Rap in turn stimulates downstream effectors such as V-Raf murine sarcoma viral oncogene homolog B1, mitogen-activated protein kinase 1 and 2 (MEK1/2), and mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 (ERK1/2), which is mainly associated with cell growth and proliferation⁴⁰. The combination of ligands for several neuropeptide receptors leads to the activation of Rho proteins and further regulates the arrangement of the actin cytoskeleton, which in turn affects cell morphology, cell motility, and intercellular interactions⁴¹. Other types of research also confirm the gene expression regulatory functions of Rho GTPase, including the c-Fos and c-Jun oncoproteins, the serum response factor, and NFκB⁴². Current research suggests that the Rho pathway is implicated in various aspects of tumor progression, particularly behaviors related to cell motility such as invasion and metastasis⁴³. Similarly, there are neuropeptide receptors coupled to α_i that act primarily by inhibiting cAMP synthesis.

When we stand at the point of the whole body, neuropeptides not only serve the role of neurotransmitters and hormones, but they can also act as signal molecules to participate in the balance of the body's homeostasis.

2.4.　 Functions of neuropeptidergic system

Neuropeptides play the following roles in human physiological activities: (1) neurotransmitters, which are involved in signaling between neurons in the central nervous system; (2) neuromodulators, which indirectly regulate the release of transmitters from synaptic endings to increase or decrease their effect in transmitting information; (3) neuroendocrine hormones, which act as signaling molecules to communicate between the central nervous system and peripheral organs, and widely regulate the physiological functions of the organism. Ultimately, neuropeptide is a signaling molecule and, due to its closed loop, the information it transmits is not unidirectional. Neuropeptides can likewise be used as signals from peripheral organs to eventually enter the brain through the blood–brain barrier (BBB) and influence brain function. In what follows we will take some examples to demonstrate the effects of the neuropeptide system on several physiological functions, with an emphasis on multi-organ communication.

Food intake is a vital and complex behavior that is regulated by various neuropeptides. So, it will be a good example to clarify the neuropeptide's mode of action. Research confirms that two main neuropeptide systems are involved in the control of food intake: NPY and POMC, the former exerting a strong orexigenic effect and the latter counteracting it⁴⁴. Arcuate nucleus (ARC) is the region most crucial to the control of feeding and energy balance and there are vast NPY and POMC neurons located in it. NPY from the ARC neurons stimulates the feeding process and reduces energy expenditure in the following ways: (1). NPY acts straightly on postsynaptic Y1R expressed on adjacent POMC neurons and inhibits their functions; (2) NPY acts on a different set of postsynaptic Y1R and Y5R-expressing neurons located in PVH and promotes their neural activity; (3) GABA and AgRP, co-released neurotransmitters of NPY, could also inhibit activation of POMC neurons. NPY neurons are projected to plentiful nuclei such as the bed nucleus of the stria terminalis, dorsomedial hypothalamic nucleus, and lateral septal nucleus and induce their neural activities⁴⁵. More importantly, melanocortin receptor agonist shows no subsequent influence on the electrical activities of NPY neurons, suggesting the dominance of NPY neurons in feeding regulation⁴⁶. What's more, these NPY neurons are highly controlled by various peripheral factors including ghrelin, leptin, insulin, peptide YY, glucagon-like peptides, and others, most of which are neuropeptides⁴⁵.

Neuropeptides are involved in the gut–brain axis, referring to the bidirectional communication between the gut and brain⁴⁷. The gut hormones PYY and PP and the enteric neuropeptide NPY regulate digestion⁴⁸. Meanwhile, gut microbiota could influence the gut–brain axis via NPY and PPY⁴⁹. Neuropeptides also play an important role in other physiological activities such as sleep, cognition, cardiovascular activity, and chronic inflammation, which we will discuss in more detail in the following section on tumor comorbidities^47,50—53.

Another important but long-time ignored function of neuropeptides is the trophic effect. Some neuropeptides were initially noted in the central nervous system only during embryonic life, suggesting a developmental stimulus. VIP has been shown to affect growth throughout the embryo, mainly because of its ability to shorten the G1 and S phases of the neuronal cell cycle⁵⁴. NPY could exert a trophic effect on cardiomyocytes characterized as a reduced degradation of protein and stimulation of protein synthesis⁵⁵. Gastrin is also considered to exert trophic effects reflexing as control of gastric mucosal thickness and stimulation of some gastric cancer⁵⁶.

It is clear from the above that the neuropeptide system is a multi-functional and highly regulated signaling system, so it is worth exploring how it is altered in the case of tumor-bearing and how this affects cancer. Solid evidence supports the multifaceted functions of neuropeptides in cancer progression (Table 1)^57—80.

3.　Neuropeptidergic signals influence TME

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Neuropeptides contribute to cancer progression, serving as hormones to promote their proliferation or serving as hemostasis challengers against anti-tumor effects. Plenty of in vitro and in vivo experiments confirm this view. Their effect on tumors may be achieved by remodeling the tumor microenvironment (TME).

Neuropeptides influence tumors through several mechanisms, which can be categorized into three primary modalities (Fig. 2): (1) paracrine: in this mode, neuropeptides are predominantly released by interneurons and interact with specific receptors on tumor cells, thereby influencing their behavior; (2) autocrine: certain tumor cells, notably those neuroendocrine tumors (NETs) or neuroendocrine carcinomas (NEC), secrete neuropeptides that act in a paracrine fashion, suggesting a self-stimulatory role in tumor progression; (3) endocrine: neuropeptides originating from the hypothalamic–pituitary axis can traverse the circulatory system, reaching the TME and modulating its characteristics and functionality. What's more, neuropeptides, despite their origin, could also act on other non-malignant cells in TME, thereby reshaping the environment and contributing to cancer progression (Fig. 2).

3.1.　 Cancer stem cells

Cancer stem cell (CSC) is a minor subpopulation of non-dividing cells in neoplastic tissues, with strong self-renewal and tumorigenic potential. Succinctly, CSCs refer to a population of tumor-initiating and treatment-refractory cell populations^81,82. An important facet of CSC studies has focused on cell–extrinsic interactions with the ambient TME. It depends on several bidirectional cellular mechanisms, such as cell-to-cell contact and ligand–receptor interactions, to drive tumor growth. When we start thinking in the context of normal physiology, nerves are tightly regulated for cell stemness. They are also considered an essential component of the human stem cell niche⁸³. It is worth discussing the influence of infiltrating peptidergic neurons and neuropeptides on CSC.

Various neuropeptides are associated with cancer stem cells. Adrenomedullin (ADM) is a vasopressor and vasodilator neuropeptide, a member of the calcitonin gene-related peptide family, which binds to calcitonin receptor-like receptor (CALCRL) to exert its functions⁸⁴. Recent studies confirm the crucial roles of ADM and CALCRL for sustaining leukemia stem cells (LSCs) in acute myeloid leukemia⁸⁵. CALCRL is diffusely distributed in LSCs and its high expression correlates to adverse outcomes in AML. What's more, CALCRL knockdown will significantly impair leukemic growth, impair colony formation, decrease LSC frequency, and enhance the potency of chemotherapeutic agents toward AML^85,86. Other studies also confirm that the expression of ADM in AML is associated with a stem phenotype, inflammatory markers, and immunosuppressive genes⁸⁷. So it's pretty clear that the ADM system is tightly associated with leukemia stem cells but right now all knowledge is fragmented. We could not picture a clear landscape from how adrenomedullin-releasing nerves interact with leukemia and their bidirectional interactions are worthy of exploring. Endothelin (ET) and its coupled receptor-endothelin receptor (ETR) are also involved in the regulation of chemotherapy resistance of cancer stem cells⁸⁸. Macitentan, a kind of antagonist for ETR, reduced cell growth in cell lines with CD133⁺ CSC⁸⁸. Whereas, endothelin-converting enzyme-1 (ECE1), which is essential for activation of ET, is also considered as the important and independent regulator for CSC. Researches confirm casein kinase 2 could induce phosphorylation of ECE1 and enhance its stability. ECE1 finally promotes CSC characteristics, including elevated expression of the stemness gene, chemo-resistance, self-renewal, colony, and spheroid formation⁸⁹.

Neuropeptides could also be important signal molecules between the communication of cancer stem cells and other TME components. The community accepts that adipocytes contribute to cancer initiation and progression, but the concrete molecular mechanism remains to be ill-defined⁹⁰. Recent researches confirm that adipocytes promote the enrichment of prostate CSCs through a cycle of autocrine amplification⁹¹. The ability of adipocytes to secrete cathepsin B (CTSB) promotes the autocrine secretion of cholecystokinin (CCK) by tumor cells. CCK secreted by tumor cells serves two purposes: when binds to adipocytes, it further promotes the secretion of CTSB, which ultimately enhances the autocrine secretion of CCK; and when applied to tumor cells, CCK contributes to the maintenance of stemness and self-renewal⁹¹.

3.2.　 Immune cells

The role of the nervous system in regulating the immune cells and immune system has long been recognized. Solid evidence also supports neuropeptides could directly regulate immune cells. For example, substance P (SP) and its corresponding receptor NK1R are universally expressed in the immune microenvironment. SP regulates immune cells and immune responses at diverse levels, from immune-cell recruitment to modulation⁹².

Neuropeptides regulate immune cell migration and recruitment mainly by influencing the expression of chemokines, and adhesion molecules. For instance, SP could induce the production of chemokines, such as monocyte chemoattractant protein-1, macrophage inflammatory proteins, and interleukin-8 (IL-8)^93—96. High concentrations of these chemokines lead to migration and recruitment of lymphocytes and monocytes. Activation of NK1R increases dendritic cell expression of the chemokine receptor CCR7, and of the adhesion molecule macrophage-1 antigen and its ligand ICAM-1^97—99. This facilitates the targeting of these cells to lymph nodes.

Neuropeptides also contribute to immune cell proliferation. Anatomy shows that peptidergic nerves innervate the bone marrow, leading to a high concentration of SP. Lately, SP binds to NK1R on bone marrow stroma to induce interleukin-1 (IL-1) and stem cell factor¹⁰⁰. Other research confirms SP could enhance bone marrow stromal stem cell proliferation via the WNT signaling pathway¹⁰¹. SP could stimulate T cell proliferation via the upregulation of interleukin-2 (IL-2)¹⁰². In vivo study shows that genetic deletion of NK1R will decrease the proliferative response of T cells¹⁰³.

Moreover, neuropeptides modulate innate immune cells' activity via numerous intracellular pathways. By upregulating the generation of cytotoxic-associated molecules and natural cytotoxicity receptors, SP improves the cytotoxicity of natural killer cells¹⁰⁴. SP may also enhance the phagocytic activity of neutrophils and macrophages through the production of reactive oxygen intermediates (ROI) and the synthesis and release of arachidonic acid metabolites^105—108. In mast cells, SP could trigger histamine and serotonin degranulation and release, and upregulate Toll-like receptor-2^109,110.

Neuropeptides also play a vital role in the modulation of adaptive immune cells. SP could enhance immunoglobulin secretion of B cells. Depletion of SP in mouse model by capsaicin and treatment with SP antagonist significantly decrease the number of antibody-secreting cells¹¹¹. Neuropeptides could regulate T cell activation and helper T cell differentiations. Via binding to NK1R on DCs, SP can induce a Th1 and T cytotoxic (CTL)-1 bias of effector T cells in mice¹¹². SP binds to NK1R on T cells and induces the production of IFN-γ, a Th1 signature cytokine. At the same time, it does not affect the secretion of Th2 cytokines, such as IL-4 and IL-5¹¹³. VIP also participates in the regulation of the Th1/Th2 balance: VIP reduces IL-12 secretion and inhibits T-bet expression, thereby reducing differentiation into Th1 cells¹¹⁴. Simultaneously, VIP promotes the expression of c-MAF, GATA-3, and JUNB, which are key regulators of Th2 cells, inhibits CXCL10, and induces the expression of CCL22, which promotes Th2 cell differentiation and recruitment to inflammatory sites¹¹⁵. Another research also confirms RAMP3 has potent effects on Th differentiation. RAMP3 signaling restricted the differentiation of Th2; however, promoted Th1 cell differentiation by inducing the expression STAT1, the key regulator of the related process¹¹⁶. Considering the balance between Th1 and other types of Th cells is critical for anti-tumor response, intervention of related neuropeptide signaling may facilitate the enhancement of antitumor immunity.

The wide distribution of neuropeptides and their receptors under physiological conditions and their close relationship with the etiology, pathogenesis, or possible treatment of immune-mediated diseases have revealed them as important parts in the field of neuroimmunomodulation. In the subsequent sections, we will discuss how neuropeptide signaling reshaped the immune microenvironment under tumor-nearing situations.

3.3.　 Endothelial cells and other stromal cells

Researches confirm neuropeptides contribute to the functional regulation of endothelial cells in TME. ETs are a family of three 21-aa peptides, mediating their action by activation of Endothelin receptor A and Endothelin receptor B, which has been confirmed to influence tumor-associated endothelial cells and matrix cells. ETs could serve as mitogens and angiogenic factors. ETs regulate multiple angiogenesis processes, including endothelial cell proliferation, migration, tube formation, and vessel renewal¹¹⁷. Upregulated expression of ETs and their cognate receptors is significantly associated with microvessel density and vascular endothelial growth factor (VEGF) expression in tumor tissues. At the level of RNA, ETs will increase VEGF mRNA expression in a time- and dose-dependent manner. Further studies also prove that ETs could induce the release of endothelial microvessels, subsequently influencing cellular inflammation, apoptosis, and endothelial nitric oxide synthase¹¹⁸.

Neuropeptides also affect some other stromal cells. For example, NPY also contributes to adipocyte differentiation and activation¹¹⁹. The browning of white adipose tissue is controlled by hypothalamic NPY neurons, what's more, white adipose tissue could also be an important source for NPY secretion¹¹⁹. Leptin, an energy-regulated peptide, is mainly produced in white adipose tissue and seldom released from the hypothalamus^120,121. Several studies have proven that leptin directly influences lipogenesis, lipolysis, and metabolism of adipocytes^122,123. It also exerts indirect effects through the modification of insulin action¹²⁴. As for fibroblasts, several neuropeptides participate in the regulation of their proliferation.

In addition to these cellular components mentioned above, neuropeptides have a more pronounced effect on the tumor itself, correlating with cancer hallmarks, and the remodeling of the TME by neuropeptides underpins their influence on tumor behaviors.

4.　Neuropeptide systems influence cancer hallmarks

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The cancer hallmarks present a theoretical framework that provides long-lasting support for rationalizing the vast complexity of cancers and their mechanisms of occurrence. Here, we will consider several examples illustrating how neuropeptide systems influence the hallmarks (Fig. 3).

4.1.　 Cancer proliferation

Cells rely on mitogenic growth signals to switch from dormant to active proliferative states¹²⁵. These signaling molecules bind to certain receptors, subsequently regulating the cell's proliferation behavior. The growth signals received by normal tissues are tightly controlled, no matter by whatever means. However, tumors spontaneously generate signaling molecules and overexpress the corresponding receptors, thereby maintaining a prolonged proliferative state, termed autocrine signaling¹²⁶. As mentioned earlier, neuropeptidergic signaling shows great trophic effects. Therefore, it is not surprising that they can also influence tumor proliferation.

Taking bombesin (BBS) as an example, back in 1985, Cuttitta et al.¹²⁷ confirmed that BBS and gastrin-releasing peptide could act as autocrine growth factors in human small-cell lung cancer via bombesin receptor (BnR). From molecular levels, BBS caused a significant increase in Sonic Hedgehog gene transcription and protein secretion¹²⁸. Activation of BnR could also transactivate the EGFR/HER family and its downstream signaling cascades¹²⁹. A similar phenomenon was observed in breast cancer. Researchers confirmed SP could induce phosphorylation of HER2 Tyr1248¹³⁰. SP treatment also induced elevation of HER-2, contributing to its overexpression¹³⁰. BBS could also act as an autocrine growth factor in some medullary thyroid, pancreatic, gastric, colorectal, and breast cancer lines¹³¹. Apart from this, tumor cells can influence the release of neuropeptides by other components in the TME, thereby regulating tumor proliferation through paracrine signaling. Glioblastoma showed high expression of Y2R and researchers also observed increased intratumoral nerve fibers contained NPY by immunohistochemistry¹³². The neuron-derived NPY would finally enhance tumor proliferation.

Neuropeptides do not always exhibit a tumor-promoting effect. For example, research has shown that NPY can inhibit the proliferation and invasion of cholangiocarcinoma and the administration of NPY receptor antagonists can block the inhibitory effect¹³³. Somatostatin (SST) and its analogs also exert an inhibitory effect on tumor proliferation. SST could suppress the synthesis and secretion of growth factors and indirectly affect tumor growth. They could inhibit hepatic GH-induced OGF-I production via SST-mediated activation of a tyrosine phosphatase leading to dephosphorylation of STAT5b and a decrease in IGF-I gene transcription¹³⁴.

4.2.　 Cancer apoptosis

Apoptosis, a type of programmed cell death, is an essential means of controlling cell counts. Accumulating evidence suggests that cancer cells could acquire resistance toward apoptosis. One common mechanism is the upregulation or activation of anti-apoptotic proteins, such as Bcl-2 and Bcl-xL. These proteins prevent the release of cytochrome c from mitochondria, inhibiting the formation of the apoptosome complex and subsequent activation of caspases, which are responsible for carrying out apoptosis. Additionally, cancer cells may exhibit dysregulation in signaling pathways that control apoptosis, such as the PI3K/Akt pathway. Moreover, cancer cells may hijack survival signaling pathways, such as NFκB, which promotes cell survival and inhibits apoptosis. By aberrantly activating these pathways, cancer cells can evade apoptosis and promote their survival and growth.

The relationship between neuropeptides and apoptosis is highly complex, and different neuropeptides can have different effects on various types of tumors. Some neuropeptides have been found to promote cell apoptosis, while others may have anti-apoptotic effects. A classic case is the role of Orexin and its receptors on tumor apoptosis. More importantly, exploring orexin-induced apoptosis reveals a novel apoptotic pathway, involving immunoreceptor tyrosine-based motifs (ITIM) and the tyrosine-protein phosphatase non-receptor type 11 (SHP2)^135,136. The interaction between orexins and OX1R in colon cancer cells induced the β/γ subunits dissociation from the Gq protein, leading to phosphorylation by Src kinases of two ITIM sites present in TM2 and TM7 of the receptor. The phosphorylated receptor then recruits and activates SHP2, which subsequently leads to the activation of p38 mitogen stress protein kinase through the RAS/MAPK signaling pathway.

Bax protein translocation in mitochondria, followed by cytochrome c release, which is involved in the formation of apoptotic vesicles. This leads to the activation of caspases 3 and 7, which results in cell death. The same situation could also be observed in neuroblastoma cells. These findings add a new dimension to the biological activities of these neuropeptides, which may have important implications for health and disease¹³⁷. As we have emphasized, the actions of neuropeptides and their receptors are tumor-context dependent. Other researchers confirm that in pancreatic cancer cells, orexin A will promote cell proliferation through the Akt/mTOR pathway while inhibiting Bcl-2/caspase 9/c-myc-mediated apoptosis in contrast¹³⁸. Methionine enkephalin (MENK), a kind of opioid peptide, enhanced the expression of opioid receptor (OGFR) and induced apoptosis of lung cancer cells by activating the Bcl-1/Bax/caspase 3 signaling pathway in vitro and in vivo. On the contrary, the regulatory effects of MENK were impeded after the blockade of the OGFR¹³⁹. And MENK could also promote apoptosis of cervical carcinoma via triggering extrinsic apoptosis signal of Fas/Caspase 3/Caspase 8 and intrinsic pathway of Bax/Caspase 9/Caspase 3¹⁴⁰. What's more, the contribution of somatostatin system to mediation of apoptosis is well studied. The binding of SST to its corresponding receptors will lead to several cytotoxic and cytostatic effects and induction of CDKs. In leukemia cells, SSTR2 exhibits apoptosis independent of p53. In other cancer cells, activation of SSTR2 induces apoptosis through the PTP-1-C-mediated signaling pathway. SP has an adverse function, while usage of NK1R antagonists could induce cell apoptosis¹⁴¹. Aprepitant, a long-history NK1R antagonist, has been proven to induce apoptosis in various types of cancer and various antitumor effects¹⁴². Researchers found that Aprepitant resulted in Caspase 8/-9-dependent apoptotic pathway activation by modifying the expression of genes involved in apoptosis and it could also abrogate the PI3K/Akt pathway¹⁴³. When we take into account the cross-talk between neuropeptides, the situation becomes even more complex. Feng investigated the effects of SP and serotonin (5-HT) on B16F10 melanoma cells and they found SP was able to inhibit the expression of the 5-HT2A receptor and upregulate the expression of NK1R¹⁴⁴. Additionally, the pro-apoptotic effect of SP could be attenuated by 5-HT2A agonists and its receptor activation¹⁴⁴.

4.3.　 Cancer angiogenesis

Just like normal tissues, tumors need sustenance in the form of nutrients and oxygen. They also require the ability to evacuate metabolic wastes and carbon dioxide. Tumor-associated vasculature addresses these problems. Tumor vessels have many unique characteristics. They are tortuous and leaky, their diameter is irregular and their walls are thin, which could be explained by the relative paucity of pericytes, or reduced pericyte function¹⁴⁵. Angiogenesis, this process is regulated by various growth factors, especially VEGF and its corresponding receptor. Recent researches confirm neuropeptides and their receptors also take part in tumor angiogenesis, not only via regulation of the release of VEGF but also by directly promoting endothelial proliferation, which has been previously discussed in detail.

The relationship between the tachykinin family and tumor angiogenesis is also abundantly learned. NK receptors are found in most arteries, small arterioles, capillaries, and post-capillary venules. Tachykinin binds to these receptors and thus plays a role in regulating microvascular permeability, regulating blood flow, leukocyte trafficking, and angiogenesis. Therefore, it is quite reasonable to speculate that the tachykinin system can influence tumor angiogenesis. Tachykinin and its receptor are highly expressed in tumor tissues and peritumor blood vessels in many cancer specimens. Peritumoral blood vessels of gliomas, medullary thyroid carcinomas, breast carcinomas, neuroblastomas, and colon carcinomas all upregulate the corresponding receptors at an extremely high rate¹⁴⁶. SP, by binding to NK1R, was able to significantly affect the structure and function of intratumor or peritumor blood vessels, which means they can promote tumor vascular flow and stromal cell development, thus facilitating tumor metastasis. In studies of colon cancer, researchers have found that neurons are not the only source of SP. Because neurons grow too slowly, there may be no perivascular nerves adjacent to tumors, and in this case, immune cells would take over the function of neurons, which are also able to secrete tachykinin to regulate the growth of tumor blood vessels¹⁴⁷. Momen Razmgah et al.⁷⁶ found that treating ovarian cancer cells A2780 with SP and aprepitant (a kind of NK1R antagonist) would influence the expression of VEGF and VEGFR. Aprepitant would significantly reduce the mRNA expression of VEGF and VEGFR genes and exogenous SP will lead to a significant increase in VEGF and VEGFR genes. As for neurokinin-B and neurokinin-3 receptor, other researchers observed that NK-B could reversibly inhibit endothelial cell vascular network assembly and opposes angiogenesis in the chicken chorioallantoic membrane¹⁴⁸. Mechanistically speaking, NK-B reduced the expression of some proangiogenic factors such as VEGF while enhanced the expression of calreticulin and vasostatin to inhibit angiogenesis¹⁴⁸. Wang et al.¹⁴⁹ designed two novel NK-B analogs: NK3R-A1 and NK3R-A2 and validated their anti-angiogenesis effect in tumors.

NPY system also shows great effects on angiogenesis on multifaceted aspects. These functions are closely related to a cleaved form of NPY, NPY_3-36. Dipeptidyl peptidase IV (DDPIV) could cleave Tyr1-Pro2 off the N terminus¹⁵⁰. Compared with other forms, NPY_3-36 shows a higher affinity to Y2R and Y5R, whose pro-angiogenic functions are in the core status¹⁵¹. Y2R participates in endothelial cell growth, viability, and migration, finally inducing angiogenesis. Y5R is also associated with vascular smooth muscle (VSMC) proliferation¹⁵². In vitro, NPY could stimulate VSMC growth over a wide range, from pmol/L to nmol/L, which could be blocked by corresponding antagonists¹⁵³. Except for proliferative regulation, NPY enhances the attachment, immigration, and capillary maturation of umbilical vein endothelial cells¹⁵⁴. Several studies confirm the important role of NPY in the illness context. For example, NPY mediates angiogenesis after ischemia and leads to revascularization of ischemic tissues¹⁵⁵. It is therefore interesting to consider how NPY regulates tumor vascular growth in the hypoxic–ischemic TME and whether it contributes to the revascularization of aberrant blood vessels in tumors. Our previous section also mentioned that endothelin has a significant effect on vascular endothelial cells. Recently, Harrison¹⁵⁶ summarized the effect of endothelin on tumor angiogenesis very well and could be a worthwhile reading reference.

It is interesting that during embryonic development, the nervous system and vascular system often develop in parallel. There exists a close interaction between the nervous and vascular systems. The growth and guidance of neurons rely on the support of the vascular system, and the interaction between neurotrophic factors and angiogenic factors plays an important regulatory role in the development of both systems. For example, angiogenic factors can influence vascular development and the formation of vascular networks, while neurotrophic factors can promote the migration and positioning of neurons. In some cases, neuropeptides can serve as the “angiogenic factors”. Endothelial cells also express various kinds of neuropeptide receptors and the proliferation will be activated when specific peptides bind to them. What's more, the transcriptome of the TME reveals that endothelial cells themselves will also overexpress several neuropeptides. It's how the autocrine loop builds. There will be great treasure waiting for us behind the mysterious veil.

4.4.　 Cancer invasion and metastasis

One of the best-known characteristics of cancer cells is their ability to invade adjacent or distant tissues, which is termed “metastasis”: tumor cells that grow in a hostile and crowded microenvironment, attempt to move and proliferate in another environment, so they initiate a series of reactions, known as the “metastatic cascade”. Firstly, they will experience serial biological and morphological changes called epithelial–mesenchymal transition (EMT), reducing their dependency on intracellular connection and increasing the ability for dissemination towards distant organs¹⁵⁷. With the abundant vascularization, newly formed or pre-existing blood vessels could serve as channels for disseminating cells^158,159. Later, tumor cells utilize a variety of motility mechanisms, chemokine gradients, and proteinases to enter and exit the circulation. After introversion, circulation, and extraversion, tumor cells lodge at secondary sites and re-establish cell connection^157,160.

When talking about the relationship between neuropeptides and tumor metastasis, there is a neuropeptide we couldn't ignore. Kisspeptin (KP), also known as KiSS-1 metastasis suppressor¹⁶¹. As the name suggests, KP plays an important role in metastasis. KP has a unique mechanism for delaying metastatic cascade that KP tends to prevent the proliferation and establishment of metastatic cells in remote sites. While other metastasis suppressors always block cell separation and emigration from the primary tumor¹⁶². At present, there is no direct evidence that KP-releasing nerves innervate tumors, suggesting that KP influences tumors mainly via endocrine means.

KP usually binds to kisspeptin receptor 1 (KISS1R), also known as GPR54 to exert its function, including suppressing motility, invasion of human cells in vitro, and metastasis. KISSR1 is coupled with Gq/11, which subsequently stimulates the PLC, induces intracellular calcium mobilization, and finally activates PKC to exert a broad-spectrum effect¹⁶³. Several studies confirm that KP signaling could inhibit metastasis via the regulation of the MAPK/ERK pathway^163,164. What's more, this signaling could also influence RhoA-ROCK activation, which is regarded as a crucial signaling pathway to regulate transformation and metastasis¹⁶⁵. Current studies seem to emphasize the effect of KP signaling on the metastatic capacity of the tumor itself, rather than how it remodels the TME to facilitate metastasis. People first observed KP has antimetastatic action in melanoma cell lines¹⁶⁶. Lee et al.¹⁶⁶ found KiSS-1 expression in metastatic melanoma cells and nonmetastatic melanoma cells: only the later cell was detected of KiSS-1 mRNA expression, indicating its antimetastatic role. In tumor cells, the expression level of KP is usually down-regulated, which may be related to the regulation of miR-21 as well as TCF21¹⁶⁷. Researchers confirm the antimetastatic role of KP in thyroid, ovary, bladder, gastric, pancreas, and lung cancers¹⁶⁸.

With the depth of related studies, KP is thought to be a promoter of tumorigenesis and metastasis in some cancer types such as breast and liver cancer^169—171. In breast cancer cells, KP signaling could induce invadopodia formation by activation of cortactin, cofilin, and membrane type Ⅰ matrix metalloproteases (MMP) and finally promote TNBC cell invasion¹⁷². What's more, KP signaling could also transactivate EGFR to promote TNBC invasion, via β-arrestin2 and MMP-9 pathway¹⁷³. Tian et al.¹⁷⁴ confirmed KiSS1 as a downstream target of the canonical TGFβ/Smad2 pathway in TNBC and is somehow necessary for TGFβ-induced cancer cell invasion. There is some in vivo evidence also consistent with the aforementioned results. Cho et al.¹⁷⁵ concluded that KISS1R haploinsufficiency delays breast tumor initiation, progression, and metastasis through its downstream RhoA signaling pathway. Plentiful clinical data also support the premetastatic role of KP and KISS1R. Compared with normal healthy breast tissue, TNBC tumor biopsies tend to display higher KiSS1/KiSS1R mRNA and protein expression¹⁷⁶.

Other peptides also participate in cancer metastasis. Neuromedin U, a secretory neuropeptide, is regarded to be involved in anoikis resistance in breast cancer, which is important for the survival of circulating tumor cells¹⁷⁷. Another research also confirmed Neuromedin U could promote cancer migration and invasion via ERK1/2 kinase activation¹⁷⁸. NPY is a well-studied neuropeptide contributing to various steps of tumor progression and several studies confirm its role in invasion and metastasis. In Ewing sarcoma, NPY participates in tumor-hypoxia-induced bone metastasis via overactivation of the RhoA pathway and cytokinesis failure¹⁷⁹. Blocking Y5R with related antagonists will prevent bone metastasis¹⁷⁹. NPY system is also associated with metastasis in prostate cancer. A transcriptomic study, which focused on the expression of NPY in prostate cancer development, demonstrated that lower NPY expression was associated with more aggressive grade, higher genomic risk, and shorter metastases-free survival¹⁸⁰. Expression of the NPY system was upregulated in pre-invasive prostate intraepithelial neoplasia, primary prostate cancer, and metastases⁷⁰. What's more, this system was increased in the perineural invasion (PNI) and extraprostatic extension area⁷⁰. But the exact molecular mechanism of how the NPY system influences prostate cancer metastasis remains to be explored. SP could also act on NK1R and induce increased expression of MMP-2 in pancreatic cancer cells, which is reflexed as enhancement of cancer migration and PNI¹⁸¹. Other research also demonstrated SP signaling could induce epithelial–mesenchymal transition in head and neck cancer, which is considered the early stage of the metastatic cascade¹⁸². More importantly, clinical studies hint at the relationship between serum levels of SP and the occurrence of metastasis but more efforts are needed to confirm the causality¹⁸³. Recently, ground-breaking research led by Tavazoie clarified a novel prometastatic mechanism mediated by the SP/NK1R axis¹⁸⁴. Researchers found the presence of a high NK1R-expressing cancer cell population in breast cancer, unexpectedly, the overactivated SP signaling led to apoptosis. Single-stranded RNAs leaked from dying cells in turn acted on the neighboring tumoral Toll-like receptor 7 and finally promoted cancer metastasis.

4.5.　 Cancer immunology

The nervous and immune systems present the body with two interfaces to perceive, integrate, and respond to environmental insults or internal injuries. In the previous section, we have discussed in detail how neuropeptides go about regulating various functions of immune cells. If scenarios are envisioned in more complex and specific situations, for example, how intertumoral peptidergic neurons go about influencing tumor immunity might provide us with a more direct understanding.

The nociceptive signaling pathway is an important mechanism for neurostimulation-mediated modulation of the tumor immune microenvironment. Nociceptive stimulation can activate the peripheral nervous system to release many neuropeptides, such as CGRP and SP¹⁸⁵. While in physiological condition, peptidergic nerves innervated immune organs and lymphoid tissues¹⁸⁶. Nervous ends release CGRP, SP, and some other peptides, which could be recognized by surface receptors on immune cells, regulating aspects of T cell differentiation in the thymus and contributing to compartmental immune responses¹⁸⁶. CGRP has complex effects on the immune system. It may exert a negative regulatory role on innate immune responses, thereby limiting tissue damage caused by inflammation^187,188. However, it can also play a pro-inflammatory role, for example, by promoting T cell homing or facilitating the migration of eosinophils to inflammatory sites through β-integrin activation^187,188. The release of CGRP by neurons can also regulate the cytokine release from macrophages or dendritic cells, thus impacting antigen presentation¹⁸⁹. Oral cancer is innervated by the sensory nerve, with CGRP as the primary neurotransmitter, which regulates tumor-related immune responses through its interaction with RAMP1. Researchers also observed increased RAMP1 expression and tumor-infiltrating lymphocytes¹⁹⁰. Animal experiments have shown that in the CRGP knockout mouse model of oral cancer, higher infiltration of CD4⁺ and CD8⁺ T lymphocytes, as well as natural killer cells and smaller tumor volumes, can be observed¹⁹¹. Similar results have also been demonstrated in melanoma. Research has indicated that nociceptive neurons are capable of detecting secretory leukocyte protease inhibitors (SLPI) released by melanoma. SLPI, in turn, triggers the release of CGRP, which acts on CD8⁺-positive T cells. As a result, these T cells increase their expression of injury immune checkpoint receptor proteins, leading to T-cell exhaustion. Blocking the CGRP receptor RAMP1 with drugs or genetically deleting the transient receptor potential vanilloid 1 (a sensory neuron ion channel) can decrease sensory signaling within the TME, reduce T cell exhaustion, inhibit tumor growth, and prolong overall survival¹⁹².

Tachykinins can promote the increase of pro-inflammatory cytokines such as IL-6 and IL-8 in the circulatory system. SP is widely studied in the immunological field and has been verified to take part in immune cell migration, immune cell proliferation, and immune cell activation^94,102,193. In essence, the reason why the tachykinin family has an important impact on immunity is that they can influence the function of hematopoietic stem cells. Broadly speaking, they can stimulate the activity of hematopoietic stem cells and promote hematopoiesis¹⁹⁴.

SP and NK1R signaling promotes the survival of activated T cells and also stimulates macrophages to release pro-inflammatory cytokines. Natural killer cells express NK1R, where SP binds to enhance cytotoxicity¹⁹⁵. T cells could synthesize SP and express the NK1R during inflammation and infection. SP/NK1R promotes T-cell proliferation in an autocrine way¹⁹⁶.

The immune checkpoint molecules are considered the main mechanism for tumors to escape from immune surveillance. PD-1/PD-L1 or Fas/Fas-L are classical ICPs that are abundantly studied. Taking PD-1 and PD-L1 as an example, when PD-L1 binds to PD-1 expressed on immune cells, it can lead to depletion of T cells and thus affect the body's anti-tumor effects. This binding triggers an immune inhibitory signal that suppresses the activation and function of T cells, limiting their ability to attack tumor cells. This immune evasion mechanism enables tumors to evade attacks from the body's immune system, increasing their survival and spreading ability. Researchers confirm that immune checkpoint molecules such as PD-L1 are expressed in neurons infiltrating into tumors. In addition, a trend toward higher infiltration of FOXP3⁺ regulatory T cells in areas harboring a higher density of PD-L1⁺ nerve fibers was observed. Another study also found that acetylcholine could downregulate the expression of PD-1 on T-cells. So, the role in which neuropeptides take part in the related process deserves studied.

4.6.　 Other cancer hallmarks

Several studies also confirm neuropeptides and their receptor take part in the acquisition of other cancer hallmarks, especially metabolic reprogramming, and bidirectional regulation between microbiomes and tumors. However, the current evidence is still insufficient and needs to be explored in greater depth.

5.　Neuropeptides influence cancer comorbidities

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Thanks to a change in attitude, we no longer think of tumors as a disease that affects a single system. Understanding how tumors interact with distant organs will be crucial for advances in the prevention and more effective treatment of human cancers¹⁹⁷. In addition to the tumor itself, patients also suffer from tumor comorbidities, and it's also an important part of antitumor therapy. Considering the universality of neuropeptides and their receptors expressed between organs and tumors, cancer-induced aberrant levels of neuropeptidergic signals may contribute to these comorbidities. Modulation of aberrant neuropeptide signaling may have multiple benefits for patients (Fig. 4).

5.1.　 Neurological dysfunctions

In our previous fragmentary description, neuropeptides in tumors can be released in an autocrine or paracrine manner by tumor cells as well as by other TME cellular components. The disruption of neuropeptide-releasing balance leads to dysfunctions of plentiful neural circuits, reflected in cancer-induced stress, depression, and other negative emotions. Some neuropeptides also can impair the BBB. For example, SP could change the expression of tight junction proteins ZO-1 and claudin-5 in brain microvascular endothelial cells^198,199. Bradykinin and angiotensin have also been proven to disrupt the BBB under several circumstances²⁰⁰. Destruction of the BBB allows more direct communication between the brain and circulatory system so neuropeptides could bypass the BBB and infiltrate the brain parenchyma. What's more, under the context of tumor-bearing organisms, many potent substances will be released to penetrate and disrupt BBB during cancer progression, which facilitates the transportation of tumor-derived neuropeptides to the brain parenchyma.

Of all the neuropeptides, SP was considered to be the most related to emotion regulation, as the limbic system, which includes the hypothalamus, amygdala, and hippocampus, overexpresses NK1Rs. Tumor-derived SP could travel to the brain via systemic circulation. After combination with SP, NK1R expressed on nerves increased the activity of the corresponding encephalic region²⁰¹. In addition to the direct effects of SP, it can indirectly affect mood by modulating the HPA axis, which plays a dominant role in stress regulation²⁰². SP could regulate cortisol secretion via the hypothalamus and adrenal gland. The intracerebroventricular injection of SP could decrease the adrenocorticotropic hormone levels in rat models²⁰³. Blocking NK1R signaling with aprepitant has been proposed as an antidepressant therapy, but its effectiveness has been questioned^204,205. However, it is a promising direction and, given the broad regulatory role of NK1R in tumors, it would also be beneficial for patients to conduct trials of the antidepressant efficacy of aprepitant in tumor patients. Other neuropeptides also contribute to these blue moods. The cerebrospinal fluid (CSF) level of NPY was significantly decreased in depressive disorder while antidepressant treatment could recover the concentration²⁰⁶. On the other hand, the administration of NPYR agonists or genetic upregulation of NPY could also exert antidepressant effects²⁰⁷. Considering NPYR has primarily a pro-tumor effect, improving the mood of patients with cancer through NPYR could do more harm than good.

5.2.　 Cancer anorexia-cachexia

Cancer anorexia-cachexia is observed in 80% of patients with advanced cancer, especially in gastrointestinal tumors. Our previous work has discussed in detail the pathogenic mechanisms of various cytokines and other particles under the context of interorgan communication²⁰⁸. Considering that one of the major mechanisms contributing to cachexia is anorexia, which is precisely regulated by neural activity, neuropeptides play an important role.

In the previous section, we have discussed in detail how neuropeptides affect food intake. NPY, acting in the hypothalamus, could activate feeding behavior by stimulating the complex sequence of behaviors from food seeking to food ingestion²⁰⁹. In the anorexia tumor-bearing rats, the concentration of NPY was drastically decreased²¹⁰. However, the administration of NPY to the corresponding encephalic region did not reverse the situation, indicating anorexia also decreases the expression of NPY receptors²¹¹. Immunocytochemical visualization and semiquantitative image analysis in another study also support this result²¹². Among all anorexigenic peptides, α-MSH has the most potent effect on tonic inhibition of feeding and body-weight gain, primarily via type 4 melanocortin receptor (MC4-R) to exert its functions²¹³. Researchers didn't confirm the upregulation of α-MSH in anorectic rats with cancer. As we know, the activity of NPY neurons itself has an inhibitory effect on the function of α-MSH, which can exert a more dominant function when the balance between the two is disturbed²¹⁴. Encouragingly, the MC4-R antagonist attenuated anorexia in a mouse model and may represent a breakthrough in clinical treatment²¹⁵. Other peptides could also influence the formerly discussed mechanism. For example, leptin exerts a direct regulatory function on the activation of NPY neurons and POMC neurons, which coexpress leptin receptors^216,217. Abnormal secretion of leptin inevitably alters its complex regulation, leaving the organism in a more disorganized state. At present, it seems we lack some clinical evidence to demonstrate the important role of NPY, as well as other neuropeptides, in cancer anorexia.

Cachexia is characterized by adipose rearrangement, muscle wasting, and metabolic disorders²¹⁵. Researchers currently believe that the development of cachexia is primarily associated with the overproduction of inflammatory factors such as interleukin-1 beta (IL-1b), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and tumor necrosis factor-alpha (TNF-α)^218,219. There is no direct evidence that neuropeptides are involved in the pathogenesis of cachexia, but they may influence the disease progression via the nerve–immunology axis.

5.3.　 Cardio-oncology diseases

In patients with a neuroendocrine neoplasm, it was common for them to suffer from carcinoid syndrome (CS). The symptoms of carcinoid syndrome, including diarrhea, difficulty in breathing, skin flush, facial lesions, and tachycardia, are caused by overexpression of serotonin and other vasoactive substances, such as tachykinin, and kallikrein²²⁰. In these patients, there is a high incidence of heart disease, termed carcinoid heart disease (CHD), mainly associated with uncontrolled fibroblast growth and fibrogenesis. The valvular lesions produced by high circulating serotonin levels are similar to those of ergot-alkaloid derivatives or fenfluramine. The role of serotonin in the development of CHD is supported by markedly elevated levels (2- to 4-fold above normal) of circulating serotonin in those with the disease. Additionally, urinary 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of serotonin, is also elevated in patients with CHD compared to carcinoid patients without cardiac involvement. A high level of circulating serotonin is associated with increased transforming growth factor-β latency-associated peptide and latent binding protein in the tissue of an involved heart valve, both of which promote fibrosis. Serotonin receptors are present on heart valves and participate in collagen synthesis in valvular interstitial cells. In experimental animal studies, long-term serotonin administration can produce morphologic and echocardiographic valvular alterations similar to those in human CHD.

Vasospasm is another cardiovascular-related acute event leading to mortality in cancer patients and this kind of comorbidity is mainly induced by anti-cancer therapy²²¹. ET-1, NPY, and other neuropeptides that exert potent vasoconstrictive functions are regarded as early biomarkers for cerebral vasospasm^222,223. Their roles and clinical implications under tumor-bearing context deserve exploration.

5.4.　 Cancer pain

Pain may be the first symptom felt by cancer patients. It is also very common that approximately 45% of all patients with advanced cancer experience pain of moderate to severe intensity²²⁴. Cancer pain could further be divided into cancer-induced bone pain, chemotherapy-induced neuropathic pain, and others, which share different pathologic mechanisms.

SP plays a predominant role in transmitting the pain impulse, and other neuropeptides such as VIP, CGRP, and CCK also participate in the process^225—227. Noxious stimulation of peripheral tissues leads to the release or generation of multiple factors including prostates, lipids, and ions. These factors can activate several classes of receptors and channels expressed by peptidergic nociceptors. If the factors excite nociceptors and generate action potentials, SP and CGRP are also released from the central projections of nociceptors in superficial laminae of the spinal cord dorsal horn, where neuropeptides activate receptors on spinal neurons to transmit painful stimuli centrally²²⁸. As we discussed in the former context, SP signaling not only participates in pain impulses but also promotes cancer proliferation via the regulation of immune cells. Recent research also confirms the mediated functions of NPY in chronic pain. Intrathecal injections of NPY modulate nociceptive stimulus, leading to analgesia in chronic models, but the exact mechanism remains exploration²²⁹. Exploring whether interfering with related neuropeptide signaling could help alleviate cancer pain might be a good direction for research.

Pain relief treatment is a must to enhance the quality of a patient's survival. When we talk about this issue, the use of opioids is an inescapable topic. They remain the main therapy for severe malignant pain, working at PNS or CNS, through blockade of presynaptic release of neurotransmitters from primary afferent terminals to trigger postsynaptic hyperpolarization of interneurons in the dorsal horn, as well as involving top-down opioidergic controls from superior centers^230,231. Exogenous and endogenous opioids exert analgesic effects by acting on MORs expressed in glutamatergic and GABAergic neurons, respectively²³². However, abuse of opioids leads to another enormous problem: opioid use disorder (OUD). Patients with OUD present with structural changes in many organs as well as loss of function, with the most serious clinical outcome being death. People with OUD have impaired executive function, impaired decision-making, impaired verbal working memory, and impaired cognitive impulsivity and cognitive flexibility²³³. More importantly, overstimulation of MOR in the medulla results in respiratory depression, leading to hypoxic brain injury²³⁴. Opioids also cause vasodilation and hypotension, directly or indirectly associated with some cerebrovascular disease²³⁵. Opioid treatment is associated with cancer recurrence in several types of cancer and opioids also contribute to cancer progression^236—238. In our previous discussion, many experiments demonstrated that long-term activation of MOR favors tumor survival. How to rationalize the use of opioids is a perennial issue. Recently, researchers also developed a hybrid peptide based on opioid and neurotensin²³⁹. This kind of hybrid peptide offered long-lasting antinociceptive activity and has a propensity to delay tolerance development, which may be a promising direction.

5.5.　 Cancer-related sleep disorder

Patients with cancer frequently suffer from sleep disorders, including insomnia, circadian misalignment, hypersomnia, somnolence syndrome, and nightmares, with a high prevalence experienced by patients with breast cancer²⁴⁰. These problems are associated with a drastic reduction in the patient's quality of life and increased mortality. Accumulating evidence links aberrant levels of neuropeptides and abnormal movement of peptidergic nerves to the influence of the processes.

The lateral hypothalamus contains numerous neural populations that receive, integrate, and fire to influence systemic physiology and behavior. Recent studies confirm nerves that release orexin-A and -B (H/O nerves) are important in stabilizing wakefulness^241,242. HO neurons are sensitive to signals arriving from the periphery including other neuropeptides such as leptin, and ghrelin, basic nutrients such as glucose, and dietary amino acids, and changes in physicochemical information such as pH and CO₂²⁴³. Two key efferent outputs from HO neurons drive changes in peripheral physiology relevant to cancer. One is through the engagement of the HPA to elicit the secretion of glucocorticoids. Additionally, HO neurons innervate multiple autonomic output nuclei in the brainstem and can signal via the sympathetic nervous system to alter the whole-body energy balance.

MCH neurons are co-mingled among HO neurons, which counters the function of HO neurons²⁴⁴. MCH neurons are active during rapid eye movement (REM) sleep, while they are silent during wakefulness²⁴⁵. Few studies have examined the relationship between the abnormal activity of MCH neurons under tumor-bearing context and sleep disorders.

5.6.　 Other comorbidities

Neuropeptides also participate in other cancer comorbidities such as bone weakness and fracture. The intimate relationship between NPY and bone metabolism has been confirmed. For example, NPY inhibits osteogenesis via the restraint of runt-related transcription factor 2²⁴⁶. But paradoxically, other studies confirm NPY could promote bone formation and fracture repair. At a low dose, NPY stimulates BMSC osteogenic differentiation²⁴⁷. Clinical observation found that in patients with fractures, NPY levels tend to increase²⁴⁸.

Neuropeptides also participate in influencing metabolic syndrome, which is occasionally accompanied by tumorigenesis. It is a disease marked by obesity, high blood pressure, and insulin resistance²⁴⁹. Recent research demonstrated neuropeptides played an important role in metabolic syndrome²⁵⁰. The NPY system plays a core role in the energy steady-state regulation system. As we formerly discussed, NPY and POMC neurons could regulate the feeding process. Recent studies also confirmed they participated in the subsequent coordination of the conversion, storage, and utilization of carbohydrates and lipids²⁵¹. More importantly, the NPY system is intimately associated with insulin resistance. Researchers found that inhibition of the hypothalamic NPY signaling would increase the secretion of insulin, suggesting the inhibitory role of NPY in the process²⁵². On the other hand, peripheral insulin also exerted an inhibitory effect on central NPY activation²⁵³. It is thought-provoking that under the insulin resistance situation, the standing increase in insulin finally led to the upregulation of NPY levels in the hypothalamus, indicating the resistance of hypothalamic NPY to feedback regulation of insulin elevation²⁴⁹. Several studies also pointed out that NPY is a strong vasoconstrictor and coordinates with norepinephrine to exert a positive time-changing effect on the heart, which is associated with hypertension²⁵⁴.

However, there is no direct evidence that NPY is associated with tumor-metabolism syndrome. Given that neuropeptide systems are implicated in various symptoms of the metabolic syndrome, it is worth exploring their effects in the context of cancer.

6.　Intervention strategy of neuropeptide system in cancers

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Neuropeptides are increasingly being developed for use as therapeutic agents in the treatment of many diseases, in particular cancer²⁵⁵. The anticancer effects of neuropeptides could be the direct result of the binding of their paired receptors, or they may be conjugated to a chemotherapy drug or radionuclide and used to target the agent to cancer cells (Fig. 5). Considering the specificity of tumor cells in expressing neuropeptide receptors, neuropeptide-based delivery systems have a promising future. However, to become an ideal delivery system, there remain some flaws that need to be overcome. Neuropeptides and their analogs are easily degraded by proteases and have some difficulty being absorbed into the bloodstream, hindering their clinical implication. To solve these problems and enhance the efficiency and selectivity of therapeutic delivery, great achievements have been made. Peptide cyclization, peptide-loaded nanoparticles, the conjugation of peptide drugs to natural or synthetic polymers, and manipulation of the amino acid sequence have been implicated in the half-life of peptide drugs and improved peptide drug delivery^256—259. What's more, the aberrant expression mode of neuropeptides and their corresponding receptors could also point to cancer initiation and progression with great possibility of serving as cancer biomarkers (Fig. 5). In the subsequent sections, we summarize the current status of some of the directions in which neuropeptides are being used in oncology therapy, as well as future perspectives, highlighting some of the dilemmas they currently face.

6.1.　 Agonist/antagonist-based cancer therapy

Considering the specific expression models of neuropeptide receptors in various cancers, targeting these receptors is wise. Solid evidence has proven the agonists/antagonists present on the market have the great potential to constrain cancer progression (Table 2^260—267). As we foresaid, there remain some neuropeptides exerting anti-tumor effects. Using agonists towards their corresponding receptors would be a potential strategy to inhibit cancer progression distinctly and safely. However, their therapeutic potential may be limited due to short plasma high-life¹⁶. Many neuropeptide analogs are designed to overcome this defect. Taking SST as an example, SST analogs have been a mainstay of therapy in functioning neuroendocrine tumors, in which hypertension is very occasional. Carcinoid syndrome is termed a phenomenon that tumor secretion of various neuropeptides and neurotransmitters such as histamine^268,269. Following the current guidelines, SST analogs are thought of as the first-line therapy for the reduction of carcinoid syndrome²⁷⁰. What's more, SST analogs could also exert antiproliferative effects and inhibit tumor growth via its corresponding receptor somatostatin receptor 2 (SSTR2), such as gastrointestinal tumors, breast tumors, small cellular lung carcinoma (SCLC), and others^271—277. But limited clinical trials prove their effectiveness. In a random clinical study, 130 patients with SCLC and positive SSTRs received chemotherapy or chemotherapy plus lanreotide; significantly better results regarding median time to progression and median survival were observed in the experimental arm²⁷⁸. Another clinical trial illustrated that a combination of docetaxel and pasireotide, a kind of somatostatin analog, showed potent clinical efficacy within metastatic castrate-resistant prostate cancer²⁷⁹. More importantly, somatostatin shows a desirable role in the management of postoperative complications. In the PREFIPS randomized clinical trial, researchers found that somatostatin was as effective as octreotide in preventing postoperative pancreatic fistula²⁸⁰. Another prospective, single-blind, placebo-controlled clinical trial demonstrated postoperative somatostatin could reduce the duration of surgical drainage and corresponding complications in gastric cancer patients who received D2 radical gastrectomy²⁸¹.

Considering that most neuropeptide receptors have tumor-promoting effects, neuropeptide receptor antagonists may have better prospects for application. For example, Pascetta et al.²⁸² confirmed using NPYR antagonists could reduce MAPK signaling, cell proliferation, cell migration, and spheroid growth and invasion. However, among all the antagonists, the NK1R antagonist, aprepitant is well studied. Researchers found Aprepitant could promote apoptosis and exert a broad-spectrum antitumor effect²⁶¹. In cancer cells, aprepitant promotes G2/M-phase cell cycle arrest and also induces apoptosis by increasing reactive oxygen species in mitochondria²⁸³. However, there is not enough clinical evidence on the anti-tumor effectiveness of aprepitant as a monotherapy. Co-administration of chemotherapy drugs and aprepitant exerts a more effective antitumor action than the administration of chemotherapy drugs alone²⁸⁴. It's reported that aprepitant could increase the sensitivity of tumor cells to doxorubicin²⁸⁵. Aprepitant could also reduce the side effects induced by chemotherapy drugs. For example, aprepitant could relieve the cardiotoxicity caused by doxorubicin²⁸⁵. Co-administration of cisplatin and aprepitant would reduce hepatotoxicity and nephrotoxicity induced by the cisplatin²⁸⁶. Several clinical experiments demonstrated aprepitant also had a potential effect on the prevention of chemotherapy-induced nausea and vomiting, which was originally designed to reduce those symptoms^287,288. Additionally, aprepitant has a high tolerance and safety. The normal cells will not be influenced after administration of a high dose of aprepitant. The IC₅₀ for normal cells such as lymphocytes and fibroblasts is higher than the IC₅₀ for cancer cells^289,290. But there remain some faults to overcome. For example, aprepitant can easily cross the BBB, which may affect the central nervous system¹⁴².

It seems that we have completed great achievement to administrate the potential effects of neuropeptide analogs on cancer therapy from pre-clinical perspectives. Another issue worth considering is how we can translate these research findings into clinical implications. To achieve this goal, high-throughput screening based on multi-omics may be a potential method. For example, Genome-wide pan-GPCR cell libraries are a kind of novel strategy that provides a powerful platform for GPCR ligand screening and facilitates the study of GPCR mechanisms and drug safety evaluation²⁹¹.

6.2.　 Cytotoxic peptide conjugate-based cancer therapy

Conventional chemotherapeutic drug treatment may be constrained in its application due to the following: multidrug resistance, toxicity to normal cells, lack of tumor selectivity, and other plights²⁹². Targeted delivery of chemotherapeutic drugs could somehow handle these questions. Nowadays, peptide-drug conjugates (PDCs) have been improved, providing small molecular weight, intensive penetration ability, increased circulation stability, low immunogenicity, and simple design, making them advantageous compared to other designs^293,294. Treatment strategies are further polarized into two main directions: cell-penetrating peptides (CPPs) and tumor-targeting peptides (TTPs). The former tend to penetrate the cell membrane via endocytosis- or receptor-mediated uptake pathways. CPPs usually transport insoluble small molecule drugs, proteins, and nucleic acids directly into cells in a non-invasive manner and without disturbing the membrane integrity, have very good tolerability, and do not evoke immunogenicity. While TTPs bind to receptors overexpressed on the tumor cells with high specificity and affinity but poor membrane permeability²⁹⁵.

Due to the heterogeneous expression of their corresponding receptors, neuropeptides unsurprisingly serve as important carriers in the design of TTP. For example, Moody et al.²⁹⁶ designed a kind of PDC, VIP-ellipticine conjugates, and confirmed its anti-tumor role in lung cancer cells via VPAC₁. They text the increased cytotoxicity of this conjugate in breast cancer cells, and received ideal results²⁹⁷. However, NPY-based TTPs are the most widely studied. Kufka et al.²⁹⁸ have developed NPY-Tubugi-1 conjugates and confirmed their antitumor role in Y1R-overexpressing cell lines, such as HT-29, Colo 320, and PC-3. Ahrens et al.²⁹⁹ developed a cleavable cytolysin-NPY conjugate and they subsequently proved this conjugate enables a receptor-specific delivery as well as a potent intracellular drug-release with high cytotoxic activity. Another research also connected methotrexate (MTX) to NPY analog and MTX-NPY conjugates showed higher potency than MTX on MTX-resistant cells³⁰⁰. BBS-based TTPs show great success in treating small cell lung cancer, due to the overexpression of BBS receptors in over 85% of SCLCs^301,302. Paclitaxel (PTX), a classical and efficient chemotherapeutic drug was crosslinked with BBS, exerting better antitumor function than unmodified PTX³⁰³. More importantly, Tao and his team developed a PTX-loaded human serum albumin nanoparticle modified with SP as the targeting ligand³⁰⁴. And this delivery system of PTX achieved active glioblastoma multiforme targeting effect and remarkable anti-tumor efficacy. Researchers also combined doxorubicin and BBS analogs to get another PDC³⁰⁵. Doxil-BN-AA1 enhanced its anti-tumor effect compared with non-modified pegylated liposomal doxorubicin³⁰⁶.

6.3.　 Peptide-receptor radionuclide therapy

Peptide receptor radionuclide therapy (PPRT) is a type of targeted radionuclide therapy based on peptides labeled with radionuclides that selectively target cancer cells³⁰⁷. Due to the presence of high levels of receptors in tumors and their ability to form ligand–receptor complexes, radiopharmaceuticals can be internalized and accumulate inside tumors more accurately¹⁶. Depending on the connected radionuclide and the type of emitted radiation, PPRT can be used for tumor killing or tumor imaging. For example, lutetium-177 (¹⁷⁷Lu) or yttrium-90 (⁹⁰Y) would release beta-particles causing DNA single-strand breaks and leading to cell death^308,309. Despite the direct effect of beta-particles on target cells, neighboring cells will also be influenced using the cross-fire effect and bystander effect, indirectly enhancing the therapeutic effect^310,311. Gallium-68 (⁶⁸Ga), copper-64 (⁶⁴Cu), and fluorine-18 (¹⁸F) could release positrons for positron emission tomography (PET) imaging. And γ-emitters such as indium-111 (¹¹¹In) or technetium-99 (⁹⁹Tc) could be used in single photon emission computed tomography (SPECT)³¹². These radionuclides could be chelated within multifarious chelators such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,20-tetra-acetic acid), DTPA (diethylenetriamine penta-acetic acid), and NODAGA (1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid)³¹³. The chelators could be further tagged to peptides like octreotide, gastrin, cholecystokinin, neuropeptide Y, and others.

In the previous section, we mentioned that NET overexpresses SSTR at high levels and logically SSA based PPRT shows great potential in the treatment. Many relevant clinical trials are underway or have been concluded to demonstrate their effectiveness (Table 3). A phase III randomized controlled trial NETTER-1 demonstrated that the combination of ¹⁷⁷Lu-DOTA-TATE and best supportive care (including Octreotide 30 mg) exceeded the monthly administration of octreotide 60 mg alone in 229 patients affected with NETs³¹⁴. ¹⁷⁷Lu-DOTATATE even showed more well-tolerated and safer than high-dose octreotide³¹⁵. In 2018, the FDA subsequently approved using ¹⁷⁷Lu-DOTATATE to treat NET patients with SSTR expression³¹⁶. ¹⁷⁷Lu-DOTATATE could also be implicated in radioiodine-refractory differentiated thyroid cancer (RrDTC) but its therapeutic response is heterogeneous³¹⁷. A recent systematic review shows that ⁶⁸Ga-DOTA-SSTR PET studies may revolutionize the routine neuro-oncology practice with the improvement of diagnostic accuracy and patient eligibility for radionuclide therapies³¹⁸.

NPY could also serve as an ideal delivered peptide. ¹¹¹In-pb12 and ^natTb-pb12 showed high binding affinity to Y1R on MCF-7 cells and their specific uptake has also been confirmed in the xenograft model³¹⁹. ⁶⁸Ga-DOTA-BVD15 have shown great potential to be used in PET imaging³²⁰. And BBS analogs labeled with ¹¹¹In, ⁶⁴Cu, ^99mTc, ⁶⁸Ga, and ¹⁸F were also texted in imaging studies³²¹. ^99mTc-BB²⁻¹⁴ visualized prostate cancer in patients³²². When using ^99mTc-RGD-BB, tumors were visualized in 6/6 breast cancer patients³²³. It remains to be determined if the imaging of GRPR will be useful in the early detection of breast and/or prostate cancer. However, there is a lack of validated large-scale clinical trials to demonstrate their potential for clinical implication.

6.4.　 Cancer biomarkers

The early detection of cancer can reduce cancer mortality and save lives to a great extent. Thus, a great deal of effort has been devoted to the exploration of new technologies to detect early signs of the disease. Cancer biomarkers cover a broad range of biochemical entities, such as nucleic acids, proteins, sugars, small metabolites, and cytogenetic and cytokinetic parameters, as well as entire tumor cells found in the fluid.

Given the stability of neuropeptides in the blood and their differential expression indicative of tumor progression, plasma neuropeptide concentrations may serve as an ideal biomarker. For example, neuroblastoma is frequently connected with elevated plasma levels of NPY, which are also associated with poor clinical outcomes³²⁴. What's more, SP was observed to be increased in ovarian tumors indicating worsened outcomes³²⁵. Another example is that calcitonin gene-related peptide is undetectable in the plasma of healthy individuals while it's drastically increased in patients with medullary thyroid cancer³²⁶. It is also interesting to note that before and after radiotherapy for prostate cancer, the levels of neuropeptides such as VIP and CGRP in the bloodstream change and increase significantly³²⁷.

Compared to neuropeptides, neuropeptide receptors may be able to provide more and more accurate information about a patient's condition, associated with polymorphism of the receptor and differential expression between normal and neoplastic tissues. Taking NPY receptors as an important pattern, back in the 21st century, Reubi used autoradiography to identify the expression of NPY receptors in breast carcinoma and they found that Y1 receptors are significantly overexpressed in 85% of primary carcinomas and 100% of lymph node metastases³²⁸. However, normal breast tissue dominantly expresses Y2 receptors, indicating the expression shift from Y2 to Y1 when cells undergo neoplastic transformation³²⁸. More importantly, cumulative evidence suggests that different NPY receptors may mediate different functions, which in turn generalizes to the following rule: (1) NPY receptors are mainly expressed in specific endocrine tumors, epithelial malignancies, and embryonal tumors; (2) tumor cells express predominantly Y1 and/or Y2 subtypes; (3) Y1 receptors are mainly involved in the modulation of cancer cell proliferation, whereas Y2 receptor activation appears to promote angiogenesis; and (4) Y5 receptors regulate cell proliferation, chemotactic migration, invasion, and contribute to chemoresistance¹⁶. Other neuropeptide receptors may serve as negative predictors. For example, according to various clinical data, a decrease in KISS1R expression is associated with poorer prognosis in cancer patients, and the downregulation of its ligand-KP is linked to recurrent cancer invasion and shorter survival^168,329.

Perhaps continuing to focus on the expression of a single neuropeptide/receptor as a tumor marker is no longer sufficient for the status quo. What we should be thinking about is how to develop more commercially available high-throughput assays for better pre-cancer diagnosis and prediction of tumor patients by combined neuropeptide/neuropeptide receptor expression levels.

7.　Conclusions

Less

Studies on the influence of the neuropeptide system in cancer initiation and progression have grown by leaps and bounds. Plenty of neuropeptides and their corresponding receptors are found in a variety of cancers and their TMEs. Some characters of them could be summarized but we often receive inconsistent findings. Neuropeptides exert distinct actions that vary from cell to cell and cancer to cancer, probably associated with different downstream signaling cascades. These signaling cascades lead to totally different “fates” of cancer cells, reflecting on cancer hallmarks. More importantly, there may be mutations in key regulatory proteins and their corresponding genes in the signaling pathway, which in turn may lead to the accumulation of signals. Take Kirsten rat sarcoma (KRAS), the most common mutated gene in colorectal cancer as an example. Once the mutations occur, the hydrolysis of GTP is interrupted and nucleotide exchange is subsequently enhanced, which further leads to the accumulation of activated KRAS protein. Staining activation of KRAS signaling finally promotes cancer progression³³⁰. Researchers also found Gαq mutations are associated with worse prognosis in uveal melanoma patients. More importantly. VGF, a kind of neuropeptide precursor, is upregulated by the aberrant Gαq/MAPK/CREB axis. VGF further binds to TGFBR2 and finally promotes endothelial–mesenchymal transition and cancer metastasis³³¹. Another important reason leading to the paradoxical roles of certain neuropeptides across different tumor types is associated with the homo-oligomerization of neuropeptide receptors, all of which are GPCRs³³². GPCRs can interact with each other to form homomers and heteromers, attaining unique expression, ligand binding, intracellular signaling trafficking, and exerting more sophisticated effects³³³. For example, MOR and DOR combine and form heteromers, which are coupled with distinct signaling pathways. MOR–DOR heteromers are associated with alterations in the induction of tolerance in response to morphine and other opioids³³⁴. It's also observed that chronic morphine administration would increase the abundance of MOR-DOR heteromers, indicating the compensatory role of oligomerization in the regulation of neuropeptide signaling³³⁵. However, oligomerization of various types of GPCRs in tumor cells has rarely been discussed, and this may also be a direction for future research. The different secretomes of different tumors likewise influence the balance of neuropeptide signaling, which is also a long-ignored reason. More importantly, different results may be obtained by using different experimental models. The experiment led by Tavazoie is the best illustration. It seems that overactivation of SP signaling leads to the death of tumor cells, but the contents released by these dying cells, such as single-stranded RNAs, subsequently promote the proliferation and metastasis of the remaining ones¹⁸⁴. Alternatively, certain neuropeptides may have more pronounced effects on immune cells or other cellular components compared to tumor cells, and these indirect impacts are also frequently overlooked by us.

Current cancer research on peptides is focused on three aspects: structure, localization, and function¹⁶. On a molecular level, studies on the structure of neuropeptides and corresponding receptors provide the solid fundament for further related studies. An exploration of localization could be demonstrated as a search for novel neuropeptide receptors discrepant expressed in certain tumors. As for functions, there are two directions to spare. First, exploration of the functions of neuropeptides and receptors under physiological conditions needs to be enhanced, which is basic for related research in a tumor-bearing context. Second, the functions of neuropeptides and receptors in cancer progression need to be well-summarized. It is also wise to rethink the probabilities for them as a potential therapeutic target.

Previous studies on neuropeptides in tumors have been largely limited to techniques such as immunohistochemistry, providing only a glimpse of the complex neuropeptide system. Different neuropeptide systems have different effects on different tumors, and these conclusions are often contradictory, deeply troubling researchers. How to distinguish the contradictory functions of neuropeptides in TME and precisely target subsets with desired functionality remains a huge challenge. To achieve this, we need to plant a more precise landscape. Single-cell transcriptomics and other omics point the way out of this dilemma. We can build a clear spectrum of the expression situation of neuropeptides and their receptors in TME with advanced techniques. Hökfelt's group³³⁶ have created a detailed landscape of the human prefrontal cortex and presented an overview of the peptidergic systems in 17 subregions of hPFC based on RNA sequencing and RNAscope. Their works contribute to great improvement in the study of neuropeptides and somehow indicate the future directions. We need plenty of landscapes for plenty of kinds of cancers. We confirmedly believe that the combination of various bioanalytical, bioinformatics, and molecular neuropharmacological tools will drive neuropeptide research to new frontiers with likely benefits toward cancer therapy.

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Year 2025 volume 15 Issue 5

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doi: 10.1016/j.apsb.2025.03.025

Receive Date：2024-07-03
Online Date：2026-09-17

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Received：2024-07-03
Revised：2024-12-09
Accepted：2025-01-03

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^bThe First Clinical Medical College of Lanzhou University, Lanzhou 730000, China

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表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Table 1 Family of neuropeptides and their role in cancer progression.

Neuropeptides family	Corresponding receptors	Expression in cancer	Functions in cancer	Action modes	Signaling pathways	Ref.
Adrenomedullin Calcitonin Amylin Calcitonin-related polypeptide	Calcitonin receptor (CTR)Calcitonin receptor-like receptor (CLR) Receptor activity-modifying proteins (RAMP)	Insulinoma, pancreatic adenocarcinoma, gastric cancer, colorectal cancer, medullary thyroid cancer, prostate cancer	Cell proliferation, metastasis, cell migration	Promotion/suppression of cancer growth through autocrine and paracrine mechanisms and possibly through endocrine mechanism	MAPK/ERK PI3K/Akt	58, 59, 62, 61, 60
Neuropeptide Y	Y1R	Glioma, glioblastoma, hemangioblastomas, breast cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer, ewing sarcoma, gastric cancer, hemangioma, head and neck cancer, leukemia, liver cancer, lung cancer, melanoma, neuroblastoma, ovarian cancer, pancreatic cancer, parathyroid adenoma, pheochromocytoma, pituitary adenoma, prostate cancer		Promotion/suppression of cancer growth through autocrine and paracrine mechanisms	MAPK/ERK, PI3K/Akt	63, 64, 65, 66, 67, 68, 69, 72, 71, 70
Peptide YY	Y2R
Pancreatic polypeptide	Y4R
Pancreatic polypeptide	Y5R
Enkephalins	μ Opioid receptor (MOR)	Ganglioglioma, glioma, meningioma, breast cancer, cervical cancer, colorectal cancer, cutaneous squamous cell carcinoma, gastric cancer, head and neck cancer, leukemia, liver cancer, lung cancer, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, pheochromocytoma, pituitary cancer, prostate cancer, renal cancer	Apoptosis, cell growth, cell migration, cell permeability, angiogenesis, immunosuppression	Stimulation/inhibition cancer progression through autocrine, paracrine, endocrine, and exocrine	MAPK/ERK	73, 74, 75, 76
Endorphins	δ Opioid receptor, (DOR)				AC/CREB
Dynorphins	κ Opioid receptor (KOR)				NFκB
Dynorphins	Nociceptin/orphanin FQ peptide receptor (NOPR)				P38/JNK/STAT
Substance P	Neurokinin receptor-1 (NK1R)	Breast cancer, ovarian cancer, pancreatic cancer, thyroid cancer, prostate cancer, glioblastoma, and astrocytoma	Cell proliferation, antiapoptosis, angiogenesis, mitogenesis, metastasis	Promotion of cancer development through autocrine, paracrine, endocrine pathways, or peripheral nervous system	MAPK/ERK AC/CREB	77, 78, 79, 80, 81
Neurokinin A	Neurokinin receptor-2 (NK2R)
Neurokinin B	Neurokinin receptor-3 (NK3R)				NFκB
Neurokinin B	Neurokinin receptor-3 (NK3R)				P38/JNK/STAT3

Table 2 Antitumor effect of neuropeptide antagonist/agonist.

Neuropeptide antagonist/agonist	Target site	Functions	Ref.
Aprepitant	NK1R	Direct antitumor effects, and prevention of chemotherapy-induced nausea and vomiting	264,265
Rolapitant	NK1R	Direct antitumor effects, chemosensitization, and prevention of chemotherapy-induced nausea and vomiting	266
Paltusotine	SSTR2	Direct antitumor effects	267
Octreotide	SSTR2	No direct antitumor effects, and prolonged survival	264
Rimegepant	CALCRL	Direct antitumor effects	269
Alvimopan	MOR	Promotion of faster recovery after surgery	270
Meclinertant	NTSR1	Direct antitumor effects	²⁷¹

Table 3 Summary of recent RCTs on PRRTs.

Study name	NCT number	Study design	Population	Arm1	Arm2	Outcomes
NETTER-2	NCT0397288	A phase 3 multi-center, randomized, open-label study	Patients with Grade 2 and Grade 3 advanced GEP-NET	Lutathera and long-acting octreotide	High dose long-acting octreotide	Progression free survival, objective response rate, time to decline total health status; duration of response, rate of adverse events, time to death
NeoLuPaNET	NCT04385992	A prospective phase II single-arm trial	Resectable PanNETs,	¹⁷⁷Lu-dotatate	NA	Postoperative morbidity, postoperative mortality
COMPETE	NCT03049189	A prospective, randomized, controlled, open-label, multicenter phase 3 study	Patients with inoperable, progressive, somatostatin receptor-positive (SSTR⁺), neuroendocrine tumors of gastroenteric or pancreatic origin (GEP-NET).	¹⁷⁷Lu- edotreotide	Everolimus	Progression-free survival, overall survival
ALPHAMEDIX02	NCT05153772	A phase 2 open label multicenter, single-arm study	Patients with positive somatostatin positive neuroendocrine tumors with no prior history of peptide receptor radionuclide therapy (PRRT naïve)	²¹²Pb-dotamtate (AlphaMedix)	NA	Objective response rate by response evaluation criteria in solid tumors, number of patients with treatment-related adverse events, median progression free survival; overall survival, time to tumor progression
	NCT03773133	A multicenter, open-label phase 1/2 study	Patients with locally advanced or metastatic cancers expressing sstr2 as identified by Satoreotide trizoxetan positron emission tomography (PET/CT) scans.	¹⁷⁷Lu-OPS201,68Ga-OPS202	NA	Maximum tolerated cumulative activity, objective response rate over the two treatment cycle
	NCT04318561	A prospective, randomized, double-blinded study	Patients with histologically confirmed metastatic, well-differentiated neuroendocrine tumors	⁶⁸Ga-dotate	⁶⁸Ga DOTA-LM3 ⁶⁸Ga-dotate	Blood pressure, heart rate, pulse oximetry, electrocardiogram QT interval, incidence of adverse effect, C_max (maximum concentration achieved in units of Bq/mL), T_max (time to achieve C_max), Standard uptake value (SUV), Lesion numbers
ETCTN 10388	NCT04234568	A multicenter randomized phase 2 trial	Patients with well differentiated somatostatin receptor-positive neuroendocrine tumor	¹⁷⁷Lu-dotatate	Triapine + ¹⁷⁷Lu-dotatate	Overall response rate, median progression free survival, plasma deoxyribonucleosides, circulating DNA and plasma hPG80
LEVEL	NCT05918302	A randomized, open-label, phase 3 international trial	Patients with progressive, advanced, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin.	¹⁷⁷Lu- edotreotide	Everolimus	Progression free survival, overall response rate, duration of response, overall survival, safety, and quality of life
COMPOSE	NCT04919226	A prospective, randomized, controlled, open-label, multicenter study	Patients with well-differentiated aggressive grade 2 and grade 3, somatostatin receptor-positive, neuroendocrine tumors of gastroenteric or pancreatic origin.	¹⁷⁷Lu-edotreotide	Capecitabine+ temozolomide	Progression free survival, objective response rate, overall survival, duration of response, disease control rate, duration of disease control

Figure 1 Signaling pathways transduced by neuropeptide receptors. The prime signaling pathways are activated by neuropeptides and the corresponding receptors involved in cellular behaviors. Activation of neuropeptide receptors regulates the production of the second messengers such as cAMP, DAG, IP3, and Ca²⁺, which subsequently activate several cytokines and induce gene regulation. PKA/CREB, Ras/MEK, PI3K/AKT, NFκB, and intracellular Ca²⁺ are considered in cell survival, proliferation, drug resistance, and apoptosis. Rho/ROCK are involved in cell motility and metastasis. JAK/STAT pathways are also involved in metastasis and angiogenesis. Abnormal levels of neuropeptides may stimulate or inhibit these cascades, inducing aberrant cellular behaviors. This figure was created using BioRender (https://biorender.com/).

Figure 2 Neuropeptides reshape tumor microenvironment. Considering the universal expression of neuropeptide and their receptors in cellular components in TME, their regulatory functions should not be ignored. Neuropeptides may regulate these cells via three main means: (1) Endocrine, neuropeptides derived from other organs enter the circulating system and finally reach TME; (2) Autocrine, tumor cells can even release neuropeptides by themselves, leading to a positive feedback loop; (3) Paracrine, intratumor peptidergic nerves release neuropeptides to TME adjacently and regulate corresponding activities, whose processes are in turn regulated by other cells and their productions. Generally, neuropeptides mainly regulate the proliferation, differentiation, mobility, and specific functions of these cells. This figure was created using BioRender (https://biorender.com/).

Figure 3 Neuropeptides influence cancer hallmarks. Neuropeptides regulate several cancer hallmarks, in both promotion and inhibition, which is content-dependent. Current studies suggest that neuropeptides have profound effects on tumor proliferation and apoptosis, tumor immunity, tumor invasion and migration, and tumor angiogenesis. The influence on other cancer hallmarks deserves the exploration. This figure was created using BioRender (https://biorender.com/).

Figure 4 Neuropeptides contribute to cancer comorbidities. Serving as neurotransmitters, neuromodulators, and hormones, neuropeptides exert great effects on the regulation of the whole body. Under the tumor-bearing content, the abnormal concentrations of neuropeptides contribute to cancer comorbidities, especially neural cognition dysfunctions. Tumor-derived neuropeptides enter the systemic circulation and enter brain parenchyma simply via specific transporters or disrupted blood–brain barrier. The aberrant concentration of neuropeptides leads to neurological dysfunctions and neuroendocrine abnormalities. Abnormalities in the body's neuropeptide levels, whether of tumor or neurological origin, influence multiple organs and participate in tumor comorbidities, such as cardiac failure, vasospasm, impaired digestion, weakened bones, fractures, and others.

Figure 5 Neuropeptide system may be an ideal target for cancer therapy. Neuropeptide receptors, whose presence on cancer cells differs from their normal counterparts, may be ideal antitumor targets. Current targeting modalities for neuropeptides can be categorized into three types: agonists/antagonist-based cancer therapy, cytotoxic peptide conjugate-based cancer therapy, and peptide-receptor radionuclide therapy. These treatment modalities play an important role in tumor killing as well as tumor imaging. In addition, neuropeptides can be used as cancer biomarkers to determine tumorigenesis, and the severity of their condition, or to inform the choice of treatment. This figure was created using BioRender (https://biorender.com/).

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