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Design principles of nanomaterials for cancer immunotherapy: a mechanistic framework across the cancer immunity cycle
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Yating Bai1, Zhihao Lan1, Nana Feng1, Zhanzhan Zhang1, Yang Liu1
Cancer Biology & Medicine | 2026, 23(4) : 541 - 558
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Cancer Biology & Medicine | 2026, 23(4): 541-558
• Review •
Design principles of nanomaterials for cancer immunotherapy: a mechanistic framework across the cancer immunity cycle
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Yating Bai1, Zhihao Lan1, Nana Feng1, Zhanzhan Zhang1, Yang Liu1
Affiliations
  • 1State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials Ministry of Education, College of Chemistry, Frontiers Science Center for New Organic Matter, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China
About Author:

Author contributions

Conceived and designed the analysis: Yang Liu, Zhanzhan Zhang.

Collected the data: Nana Feng.

Wrote the paper: Yating Bai, Zhihao Lan, Yang Lin, Zhanzhan Zhang.

Published: 2026-04-15 doi: 10.20892/j.issn.2095-3941.2025.0737
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Cancer immunotherapy has revolutionized oncology by harnessing the immune system to eliminate malignant cells, yet its efficacy remains constrained by insufficient antigen presentation, limited T cell infiltration, and the immunosuppressive tumor microenvironment (TME). Nanotechnology provides strategies to address these barriers by enabling the precise delivery of antigens, adjuvants, cytokines, checkpoint inhibitors, and nucleic acids, while protecting labile cargos and allowing for controlled release. Beyond serving as carriers, nanoparticles can regulate antitumor immunity by enhancing antigen presentation, promoting T cell priming and infiltration, and remodeling the TME. This review outlines key physiological barriers to in vivo nanoparticle delivery and the corresponding engineering optimization strategies, and systematically summarizes representative advances in using nanomaterials to enhance antigen presentation, promote T cell priming and intratumoral infiltration, and remodel the tumor microenvironment. We further discuss major translational limitations, including heterogeneous tumor accumulation, intracellular trafficking bottlenecks, safety considerations, and manufacturing consistency, and finally highlight the realizable potential of nano-immunotherapy to improve both the efficacy and specificity of cancer immunotherapy.

Cancer immunotherapy  /  nanoparticles  /  tumor microenvironment  /  T cell activation  /  immune modulation
Yating Bai, Zhihao Lan, Nana Feng, Zhanzhan Zhang, Yang Liu. Design principles of nanomaterials for cancer immunotherapy: a mechanistic framework across the cancer immunity cycle[J]. Cancer Biology & Medicine, 2026 , 23 (4) : 541 -558 . DOI: 10.20892/j.issn.2095-3941.2025.0737
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Introduction
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Cancer is a complex disease driven by dysregulated cellular processes such as uncontrolled proliferation, invasion, metabolic reprogramming, and aberrant signaling1,2. The immune system attempts to restrain tumor growth through the cancer-immunity cycle, a sequence of events initiated by the release of tumor-associated antigens (TAAs) after tumor cell death3,4. These antigens are captured by antigen-presenting cells (APCs), particularly dendritic cells, which prime T cells in lymph nodes. Activated cytotoxic T lymphocytes subsequently infiltrate tumors, recognize malignant cells, and induce cell death, thereby amplifying antigen release and sustaining immune activation5. However, the immunosuppressive tumor microenvironment (TME), encompassing tumor-associated macrophages (TAMs), regulatory T cells, fibroblasts, and other inhibitory components, often blunts antitumor immunity6,7.
To address these barriers, multiple immunotherapeutic strategies have been developed, including cancer vaccines, immune checkpoint inhibitors (ICIs), adoptive cell transfer, and cytokine-based therapies8–11. Among these, ICIs have reshaped oncology, and antibodies targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) have been approved by the U.S. Food and Drug Administration for malignancies such as melanoma, non-small cell lung cancer, and hepatocellular carcinoma12. Despite these advances, only 10%–30% of patients respond, because many tumors remain immunologically “cold”, characterized by limited immune infiltration and poor antigen presentation13. Combination regimens, such as ICIs with tyrosine kinase inhibitors or chemotherapy, have increased efficacy in select contexts but remain constrained by immune-related toxicities, including autoimmune injury to the liver, kidney, and gastrointestinal tract, stemming from disrupted immune tolerance14. Ex vivo engineering of autologous immune cells, although clinically effective in some cases, is also hampered by high cost, labor intensity, and limited scalability15. These limitations underscore the need for strategies that broaden response rates, decrease systemic toxicity, and counteract tumor immunosuppression.
Nanotechnology offers promising solutions to these challenges. Nanoparticles (NPs), including liposomes (e.g., PEGylated liposomes, cationic liposomes, and immunoliposomes), polymeric NPs (e.g., PLGA-based NPs, PEG-PLA micelles, and chitosan NPs), inorganic carriers (e.g., gold NPs, mesoporous silica NPs, and iron oxide NPs), and hybrid nanostructures (e.g., lipid-polymer hybrid NPs, cell membrane-coated NPs, and MOF-based hybrid NPs), can be engineered as precise carriers for ICIs, vaccines, nucleic acids, or cytokines, thus enhancing therapeutic accumulation at tumor sites while minimizing off-target effects16. In addition, living materials such as cells, bacteria, and algae provide emerging routes for targeted delivery. Beyond serving as delivery vehicles, nanomaterials have physicochemical properties, including size, morphology, surface chemistry, and degradability, that can directly shape cellular stress responses and innate immune signaling, which enable active participation in immunoregulation. Under appropriate formulation and administration conditions, smaller NPs generally favor lymphatic drainage and uptake by dendritic cells (DCs), whereas larger or anisotropic architectures tend to enhance local tumor retention and phagocytic capture, thereby influencing antigen presentation efficiency and the strength of innate immune priming. Moreover, surface charge and chemical functionalities regulate protein corona formation and membrane interactions, and consequently affect cellular uptake pathways, endosomal escape, and cytosolic delivery efficiency. Ligand density and spatial presentation further modulate multivalent receptor engagement and cell-type selectivity, and bias delivery toward key cellular subsets. Material composition and degradability not only determine safety profiles and in vivo clearance but also can influence TAM polarization, cytokine networks, and the immunosuppressive state of the TME by tuning the intensity and duration of local inflammation, thereby promoting a shift from immunologically “cold” tumors to a more inflamed phenotype17,18. Overall, nanotechnology offers a transformative approach to overcoming the limitations of conventional cancer immunotherapy, with the potential to expand patient benefit and enable safer, more durable treatments.
Although several high-quality reviews have summarized the applications of nanomaterials in cancer immunotherapy, including those organized around the cancer immunity cycle, this review focuses on distilling generalizable design principles that link nanoengineering parameters to underlying immunological mechanisms and translational considerations. Specifically, we first introduce the physiological barriers that NPs must overcome before exerting immune-regulatory effects. We then summarize recent advances in NP-based cancer immunotherapy, focusing on strategies to enhance antigen presentation, boost T cell priming and infiltration, and modulate the TME. Finally, we discuss the current limitations of nanomaterials in immunotherapy and outline potential directions for future development (Figure 1).
Overcoming physiological barriers to NP delivery
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Despite their promise, NP-based therapies face substantial obstacles to clinical translation. Most clinically approved NPs in oncology remain untargeted and rely on the enhanced permeability and retention (EPR) effect for passive tumor accumulation19,20. However, the clinical relevance of the EPR effect is increasingly questioned, because spontaneous human tumors typically exhibit weaker vascular abnormalities and denser stromal barriers than xenograft models21,22. Clinical imaging studies using radiolabeled or magnetic NPs have revealed heterogeneous uptake and retention, in which many particles are either trapped extracellularly or cleared by TAMs before releasing their cargo23,24. Although this extracellular distribution might be sufficient for small, diffusible drugs, macromolecules such as peptides and nucleic acids require efficient cellular internalization and cytoplasmic release to achieve therapeutic benefits. Importantly, several of these limitations are less restrictive, or even advantageous, for immunomodulatory nanomedicines. In contrast to using chemotherapeutic NPs, which must achieve widespread tumor cell penetration, delivery of cytokines or adjuvants to a small subset of APCs can initiate potent systemic immune responses25. Moreover, many immunotherapy targets, such as APCs and TAMs, reside within the TME near blood vessels and therefore are readily accessible to NPs26,27. In this setting, phagocytic clearance, traditionally viewed as a barrier, can be strategically exploited to enhance NP uptake by key immune subsets. Accordingly, next-generation nano-immunotherapies are being designed not only to circumvent but also to harness these biological processes (Figure 2).
Building on this conceptual shift from avoiding to leveraging biological barriers, researchers have developed a range of advanced delivery strategies aimed at increasing the specificity and efficiency of NP–cell interactions. One major approach, cell-type-specific targeting, is achieved by functionalizing NP surfaces with ligands, antibodies, or polysaccharides that recognize receptors overexpressed on tumor or immune cell subsets. Representative tumor-associated receptors include human epidermal growth factor receptor-2 (HER2), folate receptor (FR), estrogen receptor (ER), and androgen receptor (AR), whereas CD11c, mannose receptor (CD206), and CD16 (FcγRIIIa) are valuable for selectively targeting immune subpopulations. These receptor-targeting strategies illustrate how surface engineering can bias NP biodistribution toward desired cellular populations within the TME. For example, Liu et al. have developed immunoglobulin G-decorated immunomodulating NPs, which effectively target natural killer (NK) cells via immunoglobulin G/CD16 recognition28. Similarly, Shi et al. have reported arginine-glycine-aspartic acid-integrated mixed-shell polymeric micelles, which achieve precise tumor targeting through arginine-glycine-aspartic acid/integrin αvβ3 recognition29. Beyond these well-established targets, receptor expression can be dynamically regulated by external interventions, thus creating additional opportunities for targeted delivery. For example, radiotherapy upregulates P-selectin not only in irradiated tumors but also in distant unirradiated lesions, thereby enhancing the efficacy of P-selectin-targeted NPs and contributing to abscopal-like responses30,31. Likewise, certain chemotherapeutic agents and cytokine treatments can reshape receptor landscapes on both tumor and stromal cells. For example, doxorubicin (DOX) treatment significantly upregulates the expression of PD-L1 on tumor cells, and offers new opportunities for temporal coordination between conventional therapies and nanomedicine-based delivery32,33.
Although targeting strategies can markedly increase NP enrichment on target cells and the likelihood of cellular uptake, whether delivery translates into therapeutic efficacy ultimately depends on the extent to which the cargo can evade intracellular degradation and reach the intended site of action. After receptor-mediated endocytosis, many NPs become sequestered in late endosomes, where cargos are readily degraded in the acidic environment, thereby significantly decreasing therapeutic efficacy34. To address this challenge, researchers have developed a variety of strategies to facilitate efficient cytosolic delivery. One widely explored approach is imparting positive charges to nanomaterials, thereby exploiting the “proton sponge” effect by destabilizing endosomal membranes and facilitating escape. For example, Liu et al. have reported a polyethyleneimine-based gene delivery system that rapidly escapes endosomes after being internalized by cells and achieves efficient gene transfection35. Similarly, Meng et al. have developed lipid NPs (LNPs) incorporating imidazole lipids that enable robust cytosolic delivery of ferroptosis-associated siRNA36. Another strategy involves bypassing the lysosomal pathway altogether to enable cargos to enter cells via membrane fusion or pore formation. For example, Liu et al. have designed an arginine-rich polymer (PTn-R2-C6) that undergoes direct membrane translocation and consequently avoids endosomal entrapment37. Likewise, Cai et al. have created fusogenic liposomes (Plofsomes) that fuse with cell membranes and circumvent the endo-lysosomal route, thereby preventing lysosomal degradation38. Collectively, these innovations highlight how rational NP design can overcome key intracellular barriers and broaden the therapeutic potential of nano-immunotherapy (Table 1).
Using nanoparticles to enhance cancer immunotherapy
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Enhancing antigen presentation
A critical early step in the induction of tumor-specific adaptive immunity is the recognition and uptake of tumor-derived neoantigens by professional APCs, particularly DCs39. After activation, DCs must process and present these antigens in the context of major histocompatibility complex (MHC) molecules together with co-stimulatory signals to prime effector T cells63. However, this process is often insufficient, hindered primarily by the low immunogenicity of tumors. In this section, we briefly introduce recent advances in nanomaterials to address these limitations and incerase the efficacy of cancer immunotherapies.
Facilitating antigen delivery to APCs
The initiation of effective antitumor immunity strongly relies on antigen presentation by professional APCs. However, tumor cells often evade immune recognition by downregulating antigen expression or interfering with APC activation. A promising strategy to overcome this challenge is the simultaneous delivery of tumor-derived antigens and immune adjuvants with NP-based systems. For example, Wang et al. have reported antigen self-presenting dendritic cell vesicles, ODs/NP(cG, OVA), which have been found to significantly enhance antigen presentation in a B16-OVA melanoma mouse model. After subcutaneous injection at the tail base, ODs/NP(cG, OVA) effectively accumulated in the lymph nodes and achieved precise co-delivery of ovalbumin (OVA) and the STING agonist cyclic-di-GMP (cdGMP) to DCs via homology targeting. Consequently, ODs/NP(cG, OVA) elicited robust T cell-mediated antitumor immunity and significantly suppressed tumor growth42. Similarly, Shi et al. have reported a mannose-decorated heat shock protein (HSP)-inspired nanochaperone (nChap) for DC-targeted co-delivery of OVA and the Toll-like receptor (TLR) 7/8 agonist resiquimod (R848), which has been found to markedly increase antigen presentation and tumor suppression in a B16F10-OVA melanoma mouse model (Figure 3)41. Although promising, these strategies of extracting TAAs in vitro and delivering them in vivo are often limited by insufficient antigen representativeness and instability. A highly attractive alternative approach uses NPs to capture TAAs in situ. For example, Liu et al. have developed maleimide/folate (FA) dual-decorated antigen-capturing stapled liposomes (ACSLs) to facilitate cross-presentation of TAAs. Under irradiation, ACSL efficiently captures the neoantigen through a click reaction between the sulfhydryl group on the antigen and the maleimide residue on the ACSL. Subsequently, ACSL directs the captured TAAs to DCs via FA/FR recognition, and significantly enhances antigen presentation and immune activation40. Similarly, Ding et al. have designed a TME-responsive covalent antigen-capturing nanoplatform (TDR848@FPB), which captures TAAs in situ by forming covalent bonds with nucleophilic amino acid residues in surrounding TAAs, and significantly enhances DC maturation and T cell activation39.
Facilitating antigen presentation in APCs
After antigen delivery to APCs, a critical step in eliciting T cell activation is antigen processing and cross-presentation on MHC class I (MHC-I) molecules64,65. However, the inherently low efficiency of antigen presentation poses a major barrier to the development of effective tumor vaccines66. One promising strategy to address this challenge uses NPs to promote endo/lysosomal escape of tumor antigens, thereby increasing their cytosolic availability and enhancing MHC-I-dependent cross-presentation. For example, Xu et al. have designed lipid-based nanomachines by co-assembling photoisomerizable amphiphilic Azo-based lipidoids and helper lipids. After internalization by DCs, the lipid-based nanomachines adhere to the endo/lysosomal membrane, where UV/visible light irradiation triggers continuous trans–cis–trans isomerization of azobenzene lipids and mechanically disrupts the compartment. This process enables efficient cytosolic release of the encapsulated OVA, which subsequently forms complexes with MHC-I molecules in DCs, thereby achieving robust cross-presentation and potent T cell activation43. Importantly, after endo/lysosome escape and before loading onto MHC-I binding grooves, exogenous antigens must be degraded into short peptides of 8–13 amino acids via the ubiquitin-proteasome pathway. Therefore, promoting proteasomal degradation of TAAs further enhances antigen presentation and antitumor immunity. Moreover, Xu et al. have developed a tumor vaccine (TAgD-YVac) designed to promote targeted antigen degradation and increase cross-presentation. In this system, the model antigen OVA is first conjugated with an adaptor ligand (OVA-AHCP) that recruits E3 ubiquitin ligase, and is then encapsulated in lymph node-targeting LNPs. After uptake by APCs, OVA-AHCP is released from the LNPs, engages E3 ubiquitin ligase under the guidance of AHCP, undergoes targeted proteasomal degradation, and is ultimately cross-presented as OVA-derived peptides on MHC-I molecules with high efficiency, thereby eliciting robust T cell responses44. Collectively, these results demonstrate that nanomaterials play critical roles in enhancing cancer vaccine efficacy by promoting antigen uptake, endo/lysosomal escape, targeted degradation, and MHC-I-mediated cross-presentation by APCs.
Enhancing T cell priming and infiltration
Nanomaterials, through their ability to enhance antigen uptake and cross-presentation by APCs, facilitate the progression of antitumor immune responses into an effector phase dominated by T cells. Activated CD8+ T cells are the primary effectors of tumor-specific adaptive immunity. Once primed by APCs, these cells must infiltrate the tumor stroma and maintain sustained activity within the TME to achieve effective antitumor responses67. However, tumors often form a hostile TME or secrete immunosuppressive cytokines that hinder T cell infiltration. In addition, tumor cells may upregulate inhibitory ligands (e.g., PD-L1) or downregulate co-stimulatory signals (e.g., CD28), thereby impairing APC function and restraining the activation of infiltrating CD8+ T cells68. In this section, we summarize recent advances in nanomaterials designed to overcome these barriers, with a focus on strategies to promote T cell priming, infiltration, and functional persistence within the TME.
Facilitating T cell infiltration into tumors
Even when robustly primed, effector T cells must successfully infiltrate tumor tissue to exert cytotoxic functions. However, the physical and biochemical barriers of the TME, including abnormal vasculature, dense extracellular matrix (ECM), and immunosuppressive stromal components, substantially hinder lymphocyte entry. Consequently, many tumors exhibit an “immune-excluded” phenotype, in which activated T cells accumulate at the tumor margin but do not penetrate the parenchyma, thus resulting in ineffective immune surveillance and poor therapeutic outcomes45. Therefore, strategies that promote T cell infiltration are indispensable for effective cancer immunotherapy. One promising approach is enzymatic degradation of the ECM. For example, Zhu et al. have developed a calcium phosphate (CaP) nanocarrier for tumor-targeted co-delivery of hyaluronidase (HAase), IL-12, and anti-PD-L1. After reaching the acidic TME, the CaP matrix dissociates and releases all 3 cargo molecules. HAase degrades the ECM, thereby decreasing physical barriers, anti-PD-L1 blocks the PD-1/PD-L1 axis and relieves immune suppression, and IL-12 boosts local immune activation, thus collectively facilitating deeper T cell infiltration and augmenting antitumor immunity47. Another complementary strategy is normalizing the tumor vasculature or transiently increasing vascular permeability. For example, Yuan et al. have engineered a nano-system (V@LDL NPs) for sustained intratumoral release of the anti-VEGFR2 inhibitor vandetanib. After intratumoral injection, V@LDL NPs gradually release vandetanib within tumors, and consequently downregulate VEGFA and VEGFR2 while upregulating the vascular normalization factor VEGFR1. This remodeling of the vascular network induces vessel normalization and significantly enhances T cell infiltration into the tumor parenchyma46. Similarly, Ye et al. have developed an intelligent lipid NP (1-JK-PS-FA) that selectively responds to tumor-specific cues and releases H2S. The released H2S effectively reprograms the TME by promoting angiogenesis, increasing vascular permeability, and decreasing interstitial fluid pressure, thereby facilitating CTL infiltration69.
Counteracting inhibitory signaling
The immunosuppressive TME, largely governed by immune checkpoints such as PD-1/PD-L1 and CTLA-4, severely restricts T cell activity. Although ICIs have demonstrated notable clinical success, their systemic administration often induces immune-related toxicities70. Nanotechnology offers a promising strategy to localize ICIs within tumors, thereby increasing their therapeutic index. For example, Shuai et al. developed pH- and matrix metalloproteinase (MMP-2)-responsive polymeric micelles (sAMcPs) that co-deliver anti-PD-1 and the chemotherapeutic paclitaxel (PTX). Within the TME, sAMcP releases anti-PD-1 in response to the overexpressed MMP-2. Its positively charged micelle core is subsequently internalized by tumor cells and releases PTX in response to lysosomal acidity. Consequently, sAMcP significantly enhances T cell-mediated antitumor immunity and markedly suppresses tumor growth49. Similarly, Yantasee et al. have developed silica NPs for co-delivery of a polo-like kinase 1 (PLK1) inhibitor, volasertib, and anti-PD-L1, thus significantly enhancing tumor suppression in a non-small cell lung cancer mouse model50. Beyond the delivery of ICIs, gene-editing tools offer an alternative strategy to silence or knock down inhibitory ligand expression on tumor cells. For example, Liu et al. have developed dual-locking NPs (DLNPs) for tumor-targeted delivery of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) enzyme-PD-L1 systems (Figure 4). In the TME, the acidic pH and elevated H2O2 levels synergistically unlock DLNPs, thus enabling precise, tumor-specific gene editing and effective PD-L1 disruption. This intervention relieves immune suppression, restores T cell activity, and elicits potent antitumor immune responses71. Beyond gene editing, protein degradation technologies provide another means of decreasing inhibitory ligand expression. For example, Liu et al. have developed a lysosome-targeting chimera nanoplatform that selectively degrades PD-L1 on tumor surfaces by shuttling it from the plasma membrane into lysosomes, thereby markedly enhancing antitumor immunity in a B16F10 melanoma mouse model72.
Stimulating co-stimulatory pathways
Blocking inhibitory signals can restore T cell activity, but full and durable activation additionally requires sufficient co-stimulatory input. In the TME, however, the frequent downregulation of co-stimulatory ligands predisposes T cells to functional exhaustion73. Strategies that reinforce co-stimulatory signaling are therefore essential to sustain T cell proliferation, survival, and effector function. Nanomaterials offer a promising platform for delivering agonistic antibodies or genetic modulators to boost these pathways while minimizing systemic toxicity. For example, Huang et al. have developed an antigen-presenting platform (GO-APP) by anchoring anti-CD3 and anti-CD28 onto graphene oxide. Through dual interactions with CD3 and CD28 on T cells, GO-APP effectively mimics the immune synapses formed between APCs and T cells, and leads to robust T cell proliferation while preserving multifunctionality and potent effector activity52. Similarly, Liu et al. have designed a multifunctional nano-modulator co-decorated with anti-PD-L1 and anti-4-1BB, which simultaneously blocks the PD-1/PD-L1 pathway and activates the 4-1BB co-stimulatory pathways, and ultimately significantly enhances antitumor immunity53. In addition, upregulating the expression of co-stimulatory receptors on T cells with gene-editing tools provides an alternative strategy to facilitate T cell activation. For example, Dong et al. have reported a phospholipid NP (PL-1) that efficiently delivers OX40 mRNA to tumor-infiltrating T cells and leads to a 47.4% increase in OX40 expression on T cell surfaces. This intervention markedly boosts T cell-mediated antitumor immunity and has achieved a 60% complete response rate in an A20 lymphoma model51. Collectively, these results demonstrate that nanomaterials can systematically modulate multiple steps in the antitumor immune cascade, thus increasing T cell priming, infiltration, and functional persistence, and ultimately enhancing both the magnitude and durability of antitumor immunity.
Modulating the tumor microenvironment
Effective antitumor immunity depends not only on the activation and infiltration of effector cells but also on maintaining their functionality within the TME. However, the aberrant vasculature of tumors and the elevated aerobic glycolysis of cancer cells together generate a hypoxic and acidic milieu that severely restricts immune cell infiltration and cytotoxic activity. Concurrently, immunosuppressive cell populations, including regulatory T cells (Tregs), M2-polarized TAMs, and tumor-associated fibroblasts, further attenuate antitumor responses and promote tumor progression through diverse mechanisms74. In this section, we summarize recent advances in using nanomaterials to selectively target these immunosuppressive cell populations and remodel the TME, thereby enhancing the overall efficacy of cancer immunotherapy.
Reprogramming tumor-associated macrophages
M1-type TAMs not only secrete abundant pro-inflammatory cytokines, such as tumor necrosis factor (TNF), which promote CTL responses and suppress tumor growth, but also upregulate genes associated with antigen processing and presentation, thereby facilitating T cell activation and tumor eradication. However, within the TME, TAMs are polarized predominantly toward an immunosuppressive M2 phenotype that fosters tumor progression and inhibits antitumor immunity75,76. Reprogramming TAMs toward a pro-inflammatory (M1) state has therefore emerged as a promising strategy to remodel the TME and enhance immune responses. For example, Gu et al. have developed a sprayed fibrin gel composed of a thrombin solution and anti-CD47-loaded CaCO3 NPs (aCD47@CaCO3). When sprayed into the tumor resection cavity, the mixtures rapidly form a fibrin gel in situ, and CaCO3 continuously neutralizes local acidity, thereby driving TAM repolarization toward the M1 phenotype55. Similarly, Chen et al. have engineered locally immunomodulatory graphene dioxide (GDYO) nanosheets that reprogram TAMs by inhibiting the intracellular activation of signal transducer and activator of transcription 3 (STAT3)54. In addition, several small-molecule adjuvants have been used to modulate TAM polarization. For example, Wang et al. have reported a multifunctional nanoplatform functionalized with an M2 macrophage-binding peptide to selectively deliver imiquimod (IMD) to TAMs. This system enables sustained intracellular release of IMD, and achieves durable M1 polarization and long-term alleviation of the immunosuppressive microenvironment56. Overall, targeted TAM reprogramming is expected to reinforce local pro-inflammatory signaling and enhance antigen presentation, thereby amplifying T cell-mediated immune responses. However, clinical translation will require careful consideration of off-target inflammatory risks associated with unintended immunostimulant leakage, as well as challenges associated with batch reproducibility and process controllability during the scale-up manufacturing of multicomponent nanoplatforms.
Modulating cytokine signaling within the TME
Cytokines, bioactive small proteins secreted by both immune and non-immune cells, mediate intracellular communication, and coordinate the initiation, amplification, and resolution of immune responses. However, the frequently downregulated cytokine expression in the TME limits immune activation and effector function77. Using nanomaterials to deliver cytokines directly to tumor tissues offers an effective strategy to overcome these challenges. For example, Zhang et al. have developed an acid-sensitive nanocarrier (TSNPs) for tumor-targeted co-delivery of PTX and the pro-inflammatory cytokine IL-12. This platform prolongs the systemic circulation of IL-12 and enables decreased dosing frequency, thereby promoting local T cell activation, inducing TAM repolarization, and enhancing antitumor immunity59. Similarly, Shi et al. have presented a nanochaperone (P-nChap) for tumor-targeted delivery of denatured IL-12. After reaching the TME, P-nChap facilitates refolding of denatured IL-12 into its native conformation and subsequent release, thereby mitigating systemic toxicity and eliciting robust T cell-mediated antitumor responses57. In addition, gene-editing approaches can provide a sustained local source of immunostimulatory proteins within tumors. For example, Yu et al. have designed hybrid lipid NPs (Mn-LNPs) for tumor-targeted delivery of circular RNA encoding IL-12. After internalization, Mn-LNPs effectively scavenge intracellular reactive oxygen species (ROS) and elevate ATP levels. Consequently, enhanced RNA translation efficiency and durable IL-12 production ultimately lead to remodeling of the immunosuppressive TME and boosting of cancer immunotherapy efficacy58. Likewise, Li et al. have constructed novel lipid NPs, U-101-LNPs, for tumor-targeted delivery of IL-2F mRNA, which markedly increase IL-2 expression within the TME and significantly enhance antitumor immunity78. Despite the high efficiency of LNPs for intratumoral mRNA delivery, their in vivo fate is strongly influenced by protein corona formation and apolipoprotein E (ApoE)-mediated pathways; consequently, off-target hepatic accumulation and associated toxicity often result. To address this translational bottleneck, Guo et al. have developed morphologically engineered, flower like lipid NPs termed RLNPs. By partially replacing conventional cholesterol with R-cholesterol, RLNP effectively decreases ApoE-mediated liver uptake and enables efficient local transfection while markedly mitigating IL-12-associated hepatotoxicity. This strategy provides a feasible approach to expanding the therapeutic safety window for intratumoral cytokine mRNA delivery79.
Alleviating hypoxia and metabolic suppression
The TME is characterized by severe hypoxia and metabolic dysregulation, primarily resulting from aberrant tumor vasculature and uncontrolled tumor cell proliferation80–82. These conditions strongly suppress antitumor immunity by impairing T cell metabolism; facilitate the accumulation of immunosuppressive metabolites such as lactate and adenosine; and drive macrophages and MDSCs toward immunosuppressive phenotypes. Moreover, oxygen deprivation restricts the production of ROS and the activity of cytotoxic molecules such as perforin and granzyme B in CTLs, thereby diminishing their killing capacity. Strategies that alleviate hypoxia or reprogram tumor metabolism are therefore critical to restoring immune cell functionality and enhancing immunotherapy efficacy62. For example, Liu et al. have developed immune-modulating NPs (nanoICD/CAT) by encapsulating catalase (CAT) within a rationally designed polymer shell. After reaching the tumor tissues, the polymer layers effectively induce immunogenic cell death (ICD) of tumors, while the encapsulated CAT decomposes intratumoral H2O2 into oxygen, thereby relieving hypoxia and synergistically amplifying T cell-mediated antitumor immunity61. Similarly, Gao and colleagues have designed a TME-responsive metal-phenolic nanozyme, termed RPP nanozyme. By catalyzing the conversion of H2O2 into ROS and oxygen, while simultaneously decreasing intracellular glutathione (GSH) and lactate levels, the RPP nanozyme effectively disrupts redox homeostasis in tumor cells and consequently increases immunotherapeutic efficacy. Notably, beyond enzyme-mediated oxygen generation, direct oxygen delivery provides an alternative strategy to rapidly relieve intratumoral hypoxia83. For example, Zhou et al. have designed a biomimetic nano red blood cell system [V(Hb)@DOX] for the co-delivery of DOX and oxygen. After accumulation in tumor tissues, V(Hb)@DOX rapidly responds to acidic conditions by releasing both DOX and oxygen, thus effectively alleviating hypoxia and potentiating cancer immunotherapy62. Moreover, nanocarriers designed to deliver metabolic inhibitors offer an alternative strategy to reshape TME by interfering with tumor glycolysis, decreasing nutrient competition, and rebalancing immune–tumor metabolic interactions. For example, Chen et al. have reported a glucose metabolism-targeted formulation (NP/OXA-ASP2) for co-delivery of oxaliplatin (IV) and an aspirin prodrug to suppress glycolysis and enhance chemo-immunotherapy. In colorectal cancer, NP/OXA-ASP2 treatment has been found to inhibit glycolysis more effectively than the combination of free drugs, by decreasing lactate efflux by 27.6% and increasing the proportion of CD8+ T-cells by 153%, thereby markedly boosting antitumor immunity60. Collectively, through selective intervention targeting immunosuppressive cell populations, cytokine signaling, and hypoxia associated stress, nanomaterials provide an engineering toolkit to create a microenvironment conducive to sustained T cell function.
Summary and perspectives
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Nanotechnology has emerged as a powerful platform for advancing cancer immunotherapy. NPs, by enabling precise delivery of antigens, adjuvants, cytokines, checkpoint inhibitors, and gene-editing tools, address many limitations of conventional treatments. Their small sizes, tunable surfaces, and multifunctionality allow them to cross physiological barriers, penetrate tumors, and provide sustained or controlled release of therapeutic cargos. Beyond delivery, NPs can modulate antitumor immunity by promoting antigen presentation, enhancing T cell priming and infiltration, reshaping the TME through reprogramming immunosuppressive cells, regulating cytokine signaling, and alleviating hypoxia and metabolic stress. Owing to these unique capabilities, NPs-based immunomodulatory strategies have demonstrated robust antitumor efficacy across diverse preclinical studies. For example, InnoPCV, a personalized tumor neoantigen mRNA vaccine, entered clinical trials in 2024. This platform integrates next-generation sequencing of patient tumor samples with computational prediction to identify candidate neoantigens, which are subsequently encoded into mRNA and delivered via LNPs. This approach elicits broader and more potent neoantigen-specific T-cell responses, thereby enhancing antitumor immunity. In agreement with this mechanism, InnoPCV has induced marked neoantigen-specific T-cell responses in patients with advanced non-small cell lung cancer (NCT06497010).
Despite these advantages, several barriers limit the clinical translation of NP-based immunotherapies. Tumor heterogeneity poses a fundamental biological barrier to effective cancer immunotherapy. Among diverse tumor phenotypes, immunologically “cold” tumors predominate in most solid malignancies and are a major contributor to immune tolerance. These tumors are characterized by limited immune cell infiltration, low antigenicity, and dense stromal architecture, which collectively impair immune priming and activation. Consequently, restricted immune access and physical stromal barriers further limit immune amplification and ultimately constrain therapeutic efficacy. Despite the considerable promise of NP-based immunotherapies, multiple barriers continue to hinder their clinical translation. Tumor uptake of NPs is often highly heterogeneous, and many preclinical strategies still rely on passive delivery via the EPR effect. However, even in relatively permeable tumors, the vascular endothelium remains a substantial obstacle to efficient NP extravasation. After cellular internalization, therapeutic cargos are frequently trapped within endosomal compartments, thus decreasing cytosolic availability and therapeutic activity. Additional technical challenges include achieving precise cell-type targeting, coordinating NP-based interventions with conventional therapies, and exerting fine control over intracellular cargo release. Although multifunctional nanoplatforms offer synergistic and multimodal therapeutic benefits, increased system complexity places substantial demands on scalable manufacturing, process control, and batch-to-batch reproducibility. Finally, unresolved concerns regarding the long-term safety, biodegradation, and potential immunogenicity of nanomaterials remain major obstacles to their widespread clinical application.
In the future, several strategies may help overcome these limitations in NP-based cancer immunotherapy. i) Bioinspired nanomaterials, by emulating natural biological structures and processes, such as cell membranes, extracellular vesicles, or pathogen-associated patterns, are expected to play an increasingly important role in increasing immune recognition and delivery efficiency, and achieving more balanced immune activation with diminished off-target toxicity. Additionally, the development of nanomaterials for co-delivering complementary immunomodulators or harnessing endogenous immune pathways may elicit stronger and more durable antitumor responses. ii) The integration of personalized nanovaccines with artificial intelligence-driven analytics has substantial promise. Advances in neoantigen identification, NP design optimization, and predictive modeling of biodistribution and immune responses could enable patient-specific vaccination strategies tailored to the unique tumor and immune landscapes of individual patients. iii) Combining nanotechnology with established therapies, engineered cell therapies, or emerging modalities such as mRNA vaccines and CRISPR-based interventions may expand the therapeutic landscape. iv) Fostering sustained collaboration across nanotechnology, immunology, and oncology may realize the full potential of nano-immunotherapy, by achieving safe, durable, and broadly effective cancer treatments.
Funding
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  • This work was supported by the National Natural Science Foundation of China (NSFC; Grant Nos. 52525310, 52373143, 22077073, and 52203172), the Tianjin Science Foundation for Distinguished Young Researchers (Grant No. 24JCJQJC00290), the Key Projects of Tianjin Science and Technology (Grant No. 24ZXZSSS00150), the Academy for Advanced Interdisciplinary Studies, Nankai University (AAIS, NKU), and the Frontiers Science Center for New Organic Matter, Nankai University (Grant No. 63181206).
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Year 2026 volume 23 Issue 4
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doi: 10.20892/j.issn.2095-3941.2025.0737
  • Receive Date：2025-12-15
  • Online Date：2026-11-07
  • Published：2026-04-15
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  • Received：2025-12-15
  • Accepted：2026-03-24
Funding
This work was supported by the National Natural Science Foundation of China (NSFC; Grant Nos. 52525310, 52373143, 22077073, and 52203172), the Tianjin Science Foundation for Distinguished Young Researchers (Grant No. 24JCJQJC00290), the Key Projects of Tianjin Science and Technology (Grant No. 24ZXZSSS00150), the Academy for Advanced Interdisciplinary Studies, Nankai University (AAIS, NKU), and the Frontiers Science Center for New Organic Matter, Nankai University (Grant No. 63181206).
Affiliations
    1State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials Ministry of Education, College of Chemistry, Frontiers Science Center for New Organic Matter, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China

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Correspondence to: Zhanzhan Zhang and Yang Liu, E-mail: and
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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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