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Inhibition of PCSK9: A Promising Enhancer for Anti-PD-1/PD-L1 Immunotherapy
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Shengbo Sun1, †, Jingxin Ma2, †, Tingting Zuo3, †, Jinyao Shi1, †, Liting Sun1, Cong Meng1, Wenlong Shu1, Zhengyang Yang1, *, Hongwei Yao1, *, Zhongtao Zhang1, *
Research. Vol 7 Article ID 0488
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Research. Vol 7 Article ID 0488
• Review Article •
Inhibition of PCSK9: A Promising Enhancer for Anti-PD-1/PD-L1 Immunotherapy
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Shengbo Sun1, †, Jingxin Ma2, †, Tingting Zuo3, †, Jinyao Shi1, †, Liting Sun1, Cong Meng1, Wenlong Shu1, Zhengyang Yang1, *, Hongwei Yao1, *, Zhongtao Zhang1, *
Affiliations
  • 1Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing, China.
  • 2Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 3College of Biological Sciences and Technology, Yili Normal University, Yining, China.
Published: 2024-09-25 doi: 10.34133/research.0488
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Immune checkpoint therapy, such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade, has achieved remarkable results in treating various tumors. However, most cancer patients show a low response rate to PD-1/PD-L1 blockade, especially those with microsatellite stable/mismatch repair-proficient colorectal cancer subtypes, which indicates an urgent need for new approaches to augment the efficacy of PD-1/PD-L1 blockade. Cholesterol metabolism, which involves generating multifunctional metabolites and essential membrane components, is also instrumental in tumor development. In recent years, inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine proteinase that regulates cholesterol metabolism, has been demonstrated to be a method enhancing the antitumor effect of PD-1/PD-L1 blockade to some extent. Mechanistically, PCSK9 inhibition can maintain the recycling of major histocompatibility protein class I, promote low-density lipoprotein receptor-mediated T-cell receptor recycling and signaling, and modulate the tumor microenvironment (TME) by affecting the infiltration and exclusion of immune cells. These mechanisms increase the quantity and enhance the antineoplastic effect of cytotoxic T lymphocyte, the main functional immune cells involved in anti-PD-1/PD-L1 immunotherapy, in the TME. Therefore, combining PCSK9 inhibition therapy with anti-PD-1/PD-L1 immunotherapy may provide a novel option for improving antitumor effects and may constitute a promising research direction. This review concentrates on the relationship between PCSK9 and cholesterol metabolism, systematically discusses how PCSK9 inhibition potentiates PD-1/PD-L1 blockade for cancer treatment, and highlights the research directions in this field.

Shengbo Sun, Jingxin Ma, Tingting Zuo, Jinyao Shi, Liting Sun, Cong Meng, Wenlong Shu, Zhengyang Yang, Hongwei Yao, Zhongtao Zhang. Inhibition of PCSK9: A Promising Enhancer for Anti-PD-1/PD-L1 Immunotherapy[J]. Research, 2024 , 7 (9) : 0488 . DOI: 10.34133/research.0488
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Introduction
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Since cancer immunotherapy is discovered through inhibition of immune checkpoints by James P. Allison and Tasuku Honjo [1–3], programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have been considered important “brake” molecules in tumor immunity [4]. When PD-L1 on tumor cells binds to PD-1 on T cells, T cells enter an “exhaustion” state [5,6], and their activities, such as infiltration, activation, and cytokine production, are inhibited [7]. Based on this mechanism, immune checkpoint therapy (ICT) combined with PD-1/PD-L1 blockade prevents PD-1 and PD-L1 from interacting, restoring T cells from an exhausted state and reinvigorating the T-cell-mediated immune response against cancer cells [6]. The PD-1/PD-L1 blockade therapy has shown promising results, such as improved clinical outcomes in a variety of tumors and prolonged survival of treated individuals [8,9]. However, PD-1/PD-L1 inhibitors show substantial antitumor effects in only a small subset of patients, with most individuals exhibiting a low response rate to these treatments [10], especially those with microsatellite stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) subtypes [11]. Consequently, further investigations and more approaches for enhancing the antitumor effect of anti-PD-1/PD-L1 immunotherapy are urgently needed.
Apart from anti-PD-1/PD-L1 immunotherapy, there are close relationships between serum cholesterol levels and tumor development [12]. Cholesterol metabolism, a metabolic process widely present in mammalian cells, involves essential membrane component production and metabolites with various physiological functions [13]. Mechanistically, tumor cells are highly proliferative and require large amounts of nutrients such as cholesterol to meet their proliferative needs [14,15]. In addition, the derivatives and synthesis intermediates of cholesterol are tumor progression regulators [15,16]. As a result, serum cholesterol levels can also affect tumorigenesis to a certain degree. Drugs aimed at cholesterol metabolism for cancer treatment are a rapidly emerging field. In recent years, proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine proteinase that regulates cholesterol metabolism, has shown promising antitumor potential [17]. PCSK9 inhibition may lower serum cholesterol levels, which suggests cholesterol depletion-mediated antitumor effects [17,18]. However, inhibiting PCSK9 has demonstrated enhancing the antitumor effect of PD1/PD-L1 blockade by facilitating the infiltration of cytotoxic T lymphocyte (CTL) and excluding regulatory T cell (Treg) [19]. In 2022, Guo et al. [20] designed a tumor-targeting nanocomposite combining anti-PD1 and anti-PCSK9 effects that have shown both efficacy and safety in CRC therapy. Combining PCSK9 inhibition with anti-PD-1/PD-L1 immunotherapy represents a promising approach for cancer treatment. The key discoveries about PD-1/PD-L1 and PCSK9 are shown in Fig. 1. In addition, the commonly utilized anti-PD-1/PD-L1 inhibitors and PCSK9 inhibitors are summarized in Table 1 [21–39].
In the present review, the effects of cholesterol on tumor growth and altered cholesterol metabolism in tumor cells were first described. We then explained the relationship between cholesterol metabolism and PCSK9 inhibition and elucidated the cholesterol depletion-mediated antitumor effects of PCSK9 inhibition. The detailed antitumor mechanisms of PCSK9 inhibition combined with PD-1/PD-L1 blockades are also discussed. This review summarizes the latest developments and prospects of adjunctive therapy with anti-PCSK9 and anti-PD-1 antibodies, aiming to provide novel insights for enhancing the antitumor effect of ICT.
Mutual Influence of Cholesterol and Cancer
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Cholesterol, a crucial element of biological membranes and lipid rafts, is important in tumor proliferation and development. Cholesterol metabolism regulates the physiological processes of tumor cells, especially tumorigenic signaling pathways, ferroptosis, and the tumor microenvironment (TME) [40,41]. In addition to being regulated by cholesterol metabolism, tumor cells can also alter their own cholesterol metabolism. The cholesterol metabolism processes are reprogrammed in a direction that favors tumor growth and development. Therefore, there is a mutual influence between cholesterol and cancer.
Role of cholesterol in tumor development
In recent years, numerous studies have demonstrated that cholesterol is a mediator that regulates various signaling pathways in tumor cells. The Hedgehog signaling pathway is a key factor in tumor proliferation. The Hedgehog signaling pathway activation can lead to increased proliferation of stem or progenitor cells in tissues derived from the ectoderm [42,43]. In this pathway, cholesterol is a necessary material for the Hedgehog ligand modification [44]. It combines with palmitate to form a dual lipid adduct and attaches to the Hedgehog precursor protein [45]. After modification, the mature Hedgehog protein binds to the cell membrane and performs subsequent functions [42,46]. In addition, cholesterol also functions in the Wingless and Int-1 (Wnt) signaling pathway, which is compatible with Hedgehog signaling and plays an important role in cell proliferation, polarity, and differentiation [47–50]. The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway is another important signaling pathway involved in regulating cell survival, growth, metabolism, and angiogenesis [51]. Cholesterol can activate the PI3K/AKT pathway by binding to and stabilizing receptor tyrosine kinase (RTK), particularly epidermal growth factor receptor (EGFR) and ErbB2, which are overexpressed in many cancers [52]. Cholesterol can also modulate the localization and activity of AKT by affecting lipid rafts, the cholesterol-rich regions on the cell membrane that serve as platforms for signal transduction [53]. Other signaling pathways activated by increased cholesterol, such as the mitogen-activated protein kinase (MAPK), Kirsten rat sarcoma viral oncogene homolog/mitogen-activated protein kinase/extracellular signal-regulated kinase (KRAS/MEK/ERK), and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathways, have also been shown to be related to tumorigenesis [12]. Thus, cholesterol performs indispensable functions in tumor development via various tumorigenic signaling pathways (Fig. 2A).
The TME is a special metabolic unit that includes cellular components (tumor cells, immune cells, and stromal cells) and intercellular contents [54]. Recent studies have increasingly shown that the TME is crucial in tumor occurrence, development, migration, recurrence, and therapeutic efficacy [55]. It is widely accepted that the TME is a key evolutionary and physiological process in tumor progression and cancer therapy and possesses great research and clinical prospects [56]. Cholesterol metabolism sensibly affects immune cell functions in the TME [57]. Cholesterol-derived metabolites facilitate various tumor-associated events in the tumor-infiltrating immune cells (TIICs) [58]. Cholesterol is also reported to cause CD8+ T-cell exhaustion in the TME via up-regulated levels of inhibitory receptors such as PD-1, lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin domain and mucin domain-3 (TIM-3), and 2B4 (CD244), which are affiliated with the expression of cytokines such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and granzyme B (GzmB) [59]. In addition, the level of cholesterol in the TME is closely correlated with the low-density lipoprotein receptor (LDLR), a key membrane receptor regulating tumor growth, and the process of cholesterol metabolism is reprogrammed in tumor cells [60,61]. The relevant mechanisms will be systematically discussed in the following sections. Thus, cholesterol also has nonnegligible effects on the TME (Fig. 2B).
Ferroptosis has emerged as a prominent topic in cancer research since it was defined as an iron-dependent regulated cell death (RCD) by Dixon et al. in 2012 [62,63]. In tumor cells, normal iron metabolism is reprogrammed to elevate the level of free iron to satisfy growth needs [64]. Although the function of cholesterol in ferroptosis remains ambiguous, some intermediate metabolites and enzymes involved in the biosynthesis of cholesterol have demonstrated a crucial role [65]. The intermediate metabolites include isopentenyl-pyrophosphate (IPP), farnesyl pyrophosphate (FPP), and squalene. IPP is a component of selenoprotein synthesis and is related to selenocysteine-specific transfer ribonucleic acid (sec-tRNA) stabilization, thereby facilitating ferroptosis inhibition [66,67]. FPP is a precursor of coenzyme Q10 (CoQ10), which sensibly suppresses the ferroptosis [68,69]. Squalene epoxidase (SQLE) is a key enzyme involved in cholesterol biosynthesis. SQLE loss causes squalene accumulation in cholesterol auxotrophic lymphomas, thereby inhibiting ferroptosis [70]. These findings suggest that cholesterol indirectly affects ferroptosis via intermediate metabolites and enzymes during cholesterol biosynthesis (Fig. 2C).
Altered cholesterol metabolism in cancer
In normal cells, cholesterol metabolism, involving biosynthesis, uptake, efflux, and storage, is a necessary and complicated biochemical process [15,71]. The cholesterol biosynthesis pathway initiates with the mitochondrial production of acetyl-CoA (acetyl coenzyme A). This compound condenses to form acetoacetyl-CoA (acetoacetyl coenzyme A), which is then transformed into HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme-A) by HMG-CoA synthase. In the cytoplasm, HMG-CoA reductase (HMGCR), a rate-limiting enzyme, reduces HMG-CoA to mevalonate (MVA). MVA is phosphorylated and decarboxylated to IPP, which polymerizes into FPP. FPP dimerizes to squalene, which cyclizes to lanosterol, the precursor to cholesterol via Bloch or Kandutsch–Russel pathways [55]. The absorption process of cholesterol uptake is facilitated by Niemann–Pick C1-like1 (NPC1L1) proteins in the intestine and LDLR in the plasma [72,73]. NPC1L1, a glycosylated membrane protein with multiple spans, is uniquely expressed on the apical region of enterocytes and human hepatocytes, while LDLR is expressed on the basolateral surface of most cells. Cholesterol uptake from extracellular sources is mediated by both pathways via the clathrin-dependent mechanism [72]. The clathrin-mediated pathway in mammalian cells is the major endocytic pathway that transforms ligand proteins via clathrin-coated vesicles [74]. Biosynthesis and uptake are the 2 main pathways related to tumor development.
In tumor cells, cholesterol metabolism processes are reprogrammed in a direction that favors tumor growth and development. Since cholesterol is beneficial for the growth and development of tumor cells [14,75], tumor cells can increase cholesterol levels in various ways, thereby satisfying their own growth needs. For example, cholesterol biosynthesis and uptake are enhanced in tumor cells [76,77]. Several enzymes regulating cholesterol biosynthesis, such as HMGCR and sterol regulatory element binding protein (SREBP), are substantially elevated in various cancers [78–80]. SREBP includes 3 isoforms, SREBP1a, SREBP1c, and SREBP2 [81]. SREBP1 is a regulator of fatty acid synthesis, and SREBP2 is related to cholesterol biosynthesis initiation and uptake [82]. SQLE is also sensibly up-regulated in pancreatic cancer [83], promoting squalene cyclization in cholesterol biosynthesis. Some signaling pathways involving cholesterol biosynthesis can also be overactivated in tumor cells. The PI3K/AKT pathway is one of these pathways [84], and its activation contributes to tumor occurrence, proliferation, invasion, and migration [51]. However, some tumor cells can accelerate cholesterol uptake via NPC1L1. NPC1L1-knockout mice reportedly acquire resistance to colorectal tumorigenesis [85]. Interestingly, some lymphoma cells acquire cholesterol in a manner dependent on the cholesterol uptake pathway. These cells satisfy their proliferative needs by up-regulating the expression level of LDLR [70], thereby promoting cholesterol uptake via LDLR-mediated absorption in plasma. In addition, tumor cells can maintain high cholesterol levels in the TME by dysregulating cholesterol efflux [86,87] and enhancing cholesterol esterification [88,89]. More details can be found in Refs. [14, 15]. In brief, tumor cholesterol metabolism can be altered in various ways (Fig. 3). Targeting altered cholesterol metabolism represents a promising choice for tumor treatment.
Inhibition of PCSK9 Suppresses Tumor Growth
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Proprotein convertases (PCs) are a specialized class of serine proteinases that facilitate the activation of inactive secretory protein precursors [90]. PC cleaves these precursors and converts them into active peptide/protein or multifunctional fragments [90]. PCSK9, which belongs to the PC family, is the ninth member programmed by the gene PCSK9 located on chromosome 1 [91,92]. Since PCSK9 was first reported in 2003 [92], it has become a promising target for treating dyslipidemia [93]. Research indicates that inhibiting PCSK9 reduces serum low-density lipoprotein cholesterol (LDL-c) by promoting the degeneration of LDLR [94,95]. Currently, evolocumab and alirocumab, 2 monoclonal antibodies targeting PCSK9, have received Food and Drug Administration (FDA) approval for treating hypercholesterolemia [96]. Since serum cholesterol levels are closely related to tumor proliferation and development, the inhibition of PCSK9 can suppress tumor growth to a certain extent by lowering serum cholesterol levels (Fig. 4).
Biological structure of PCSK9
The functions of enzymes are closely related to their biological structure. Determining the biological structure of PCSK9 is essential before understanding its role in cholesterol metabolism. The 3-dimensional structure of PCSK9 includes 3 distinct functional regions: a prodomain, a catalytic domain, and a C-terminal cysteine/histidine-rich domain (CHRD) [97,98]. After secretion from the endoplasmic reticulum (ER), PCSK9 remains connected to its prodomain [92]. The prodomain plays a vital role in the efflux of PCSK9 from the ER [99]. By interacting with LDLR, the catalytic subunit directs it toward lysosomal degradation, which prevents LDLR from circulating to the cell surface [100,101]. The biological function of PCSK9 mainly depends on the catalytic subunit. CHRD consists of 3 tandem repeats, namely, M1, M2, and M3. The M2 repeat interacts with the major histocompatibility protein class I (MHC I) [99]. Besides, cytosolic adenyl cyclase-associated protein 1 (CAP1), a protein with structural homology to CHRD, is considered to bind to the M1 and M3 domains, thereby enhancing PCSK9 activity and LDLR degradation [102,103]. More details of the biological structure of PCSK9 are available in the literature [99].
Physiological role of PCSK9 in cholesterol metabolism
For decades, PCSK9 has played a vital role in increasing serum cholesterol levels [104]. The physiology of PCSK9 is well developed by researchers, and its mechanisms are widely used for treating atherosclerosis and preventing atherosclerotic cardiovascular events [104]. PCSK9 promotes LDLR degradation mainly via an extracellular mechanism [105,106]. In this pathway, the interaction occurs between PCSK9 secreted into plasma and LDLR located on the plasma membrane. The EGF-like repeat homology domain-A (EGF-A) and β-propeller domain of LDLR interacts with the catalytic subunit of secreted PCSK9 [97,107]. The N-terminal region of the first EGF-A domain of LDLR is specifically bound by the catalytic domain of PCSK9. This interaction occurs at the plasma membrane and requires the presence of calcium ions, resulting in the generation of the PCSK9/LDLR composite [108]. After that, the complex combined with LDL is transferred from the cell membrane to the endosome via a clathrin-mediated pathway. In addition, experiments demonstrated that the PCSK9/LDLR complex interacting with CAP1 can enter cells by caveolin-dependent endocytosis [103]. Within endosomes, the acidic conditions sensibly boost the binding affinity of PCSK9 and LDLR due to electrostatic interactions [109,110]. Subsequently, LDL detaches from LDLR, and PCSK9 targets LDLR to the lysosome for degradation [111]. If PCSK9 does not bind to LDLR on the plasma membrane, after LDL is released into the endosome, LDLR will be recycled to the hepatocyte membrane and continue to deliver LDL for degradation [111]. In addition, some evidence shows that PCSK9 also enhances LDLR degradation via an intracellular pathway [112]. In this pathway, newly synthesized PCSK9 interacts with intracellular LDLR in the trans-Golgi network and directly targets it for the lysosomal degradation [113,114]. Poirier et al. [112] reported that blocking the transport of molecules from the trans-Golgi network to lysosomes via clathrin light-chain siRNAs (small interfering ribonucleic acid) sensibly prevented LDLR degradation in a PCSK9-dependent manner. Therefore, PCSK9 can increase serum cholesterol levels by enhancing the degradation of LDLR via both extracellular and intracellular pathways.
Inhibition of PCSK9 promotes cholesterol depletion-mediated antitumor effects
Cholesterol is a universal element of the cell membrane and plays a regulatory role in tumorigenesis. In contrast, current studies suggest that higher serum cholesterol levels are associated with an increased risk and extent of tumor progression [12]. A Korean prospective study found that higher serum cholesterol levels are linked to prostate and colon cancer in men, as well as breast cancer in women [115]. Additionally, a Mendelian randomization study showed that higher serum LDL levels are linked to an increased risk of renal cancer [116]. On the other hand, PCSK9 is a PC that facilitates LDLR degradation. Inhibition of PCSK9 promotes LDLR recycling instead of degradation, thereby lowering serum cholesterol levels through the cholesterol uptake process. Thus, the inhibition of PCSK9 can suppress tumor development to a certain degree by lowering serum cholesterol levels. Targeting PCSK9 is not only effective for the treatment of hypercholesterolemia but also promising for cancer therapy.
Corresponding to the effects of cholesterol on tumor growth, PCSK9 inhibition also has cholesterol depletion-mediated antitumor effects by regulating tumorigenic signaling pathways, ferroptosis and the TME. For example, Jin et al. reported that flubendazole, an anthelmintic drug, inhibited the Hedgehog signaling pathway by directly interacting with PCSK9 [117]. Wang et al. [118] demonstrated that PCSK9 facilitates the progression and metastasis of colon cancer by regulating epithelial–mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. Shu et al. [119] showed that Lin28b, an RNA-binding protein, promoted the growth of pancreatic ductal adenocarcinoma by inducing PCSK9's production. These findings reflected the mutual influence between PCSK9 and tumorigenic signaling pathways. Regarding the role of PCSK9 in ferroptosis, Alannan et al. [120] indicated that PCSK9 inhibition enhanced the vulnerability of liver cancer cells to iron-triggered lipid peroxidation, thereby triggering cell death by ferroptosis. Zhuang et al. [121] demonstrated that in abdominal aortic aneurysm neck, PCSK9 was highly expressed and some ferroptosis-related genes were also down-regulated, indicating the relationship between PCSK9 and the ferroptosis-related genes. Moreover, Yuan et al. [122] reported that PCSK9 inhibits LDLR-mediated T-cell receptor (TCR) recycling and signaling, thus down-regulating CD8+ T-cell-mediated antitumor response. The results suggested that PCSK9 also plays a role in the TME. Therefore, PCSK9 inhibition might offer a novel strategy for preventing and treating cancer by modulating cholesterol metabolism. However, further research is required to clarify the underlying mechanisms and clinical implications of PCSK9 in cancer biology [123].
Inhibition of PCSK9 Potentiates Anti-PD-1/PD-L1 Immunotherapy
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Apart from restraining tumor growth via the cholesterol depletion-mediated pathway, more studies have shown that PCSK9 inhibition can also potentiate the effects of PD-1/PD-L1 blockades, which suggests a novel approach for tumor treatment (Table 2). Anti-PD-1/PD-L1 immunotherapy is a type of cancer treatment that blocks the interaction between PD-1 and PD-L1 and restores the T-cell antitumor function [124]. However, the effectiveness of this therapy is restricted by the minimal expression of PD-L1 on tumor cells and the immunosuppressive nature of the TME [125]. It has been proven that inhibition of PCSK9 can maintain MHC I recycling and facilitate LDLR-mediated TCR recycling and signaling, thereby improving the effectiveness of PD1/PD-L1 blockades (Fig. 5) [122,126]. Moreover, PCSK9 inhibition can also modulate the TME by affecting the infiltration and exclusion of immune cells [19].
PCSK9 disrupts the recycling of MHC I by promoting MHC I degradation
MHC I is a membrane-bound glycoprotein crucial in antigen presentation and immune recognition [127]. Intracellular protein-derived peptides are presented to CD8+ T cells by MHC I molecules, which can then activate cytotoxic responses against infected or neoplastic cells [127]. The function and expression of MHC I are regulated by diverse factors, including the availability of peptide ligands, the activity of the antigen-processing machinery, and the recycling of MHC I molecules from the endosomal compartment to the cell membrane [128].
PCSK9 influences cholesterol metabolism by attaching to LDLR and directing it to lysosomes for degradation. However, PCSK9 interacts with other membrane receptors, such as MHC I, and affects their trafficking and stability [126]. The molecular mechanism by which PCSK9 disrupts the recycling of MHC I is similar to that of LDLR [126]. PCSK9 binds to the EGF-A domain of MHC I and competes with beta-2-microglobulin (β2m) for the same binding site [129]. By physically blocking the MHC I–β2m interaction, PCSK9 causes MHC I to be sorted into the lysosomal pathway instead of recycled back to the cell surface [126]. In the lysosome, MHC I is degraded by acid hydrolases, resulting in reduced MHC I expression and impaired antigen presentation [127]. This mechanism is independent of the role of PCSK9 in regulating LDLR levels, as it occurs even in the presence of cholesterol supplementation [126].
The disruption of MHC I recycling by PCSK9 has important implications for cancer immunotherapy, as it reduces the capacity of tumor cells to present antigens to CD8+ T cells and evade immune surveillance. By inhibiting PCSK9, either genetically or pharmacologically, MHC I recycling is restored, and antigen presentation is enhanced. This improves the effectiveness of ICT for cancer, such as anti-PD-1/PD-L1 blockade, which aims to revive the antitumor activity of T cells by preventing the PD1 and PD-L1 interaction [126]. PCSK9 inhibition can also synergize with other strategies that increase the expression or function of MHC I, such as IFN-γ, histone deacetylase inhibitors, or proteasome inhibitors [99,126]. Therefore, targeting PCSK9 represents a novel approach to modulate MHC I expression and enhance the antitumor effect of ICT.
Promotion of LDLR-mediated recycling and signaling
In addition to disrupting the recycling of MHC I, PCSK9 also affects the recycling and signaling of TCR, which are essential for the activation and function of T cells [122]. The TCR is a heterodimeric protein complex comprising α and β chains that recognize peptide–MHC complexes on antigen-presenting cells and initiate intracellular signaling cascades that lead to T-cell proliferation, differentiation, and cytokine production [130]. The expression and function of TCR are regulated by diverse factors, including the availability of peptide ligands, the activity of the antigen-processing machinery, and the recycling of TCR from the endosomal compartment to the cell membrane [131,132].
LDLR mediates the uptake of LDL and regulates cholesterol metabolism. However, LDLR also plays a role in TCR recycling and signaling, as it interacts with TCR and facilitates its retrieval from endosomes to the plasma membrane [122,133]. LDLR is located on T-cell membranes and binds to TCR via its EGF-A domain [134]. This interaction takes place at the plasma membrane and necessitates the presence of calcium ions, resulting in the formation of the LDLR–TCR complex [134,135]. After that, the complex is taken into the endosome via clathrin-mediated endocytosis [122]. In the endosome, LDLR and TCR dissociate, and LDLR returns to the cell surface, transporting TCR [122]. This process allows TCR to be reused for antigen recognition and signaling, thereby enhancing the antitumor activity of T cells.
PCSK9 regulates cholesterol metabolism by attaching to LDLR and directing it to lysosomal degradation. However, PCSK9 can also interfere with TCR recycling and signaling by attaching to LDLR and preventing its interaction with the TCR [122]. PCSK9 interacts with the EGF-A domain of LDLR and competes with TCR for the same binding site [136]. By blocking the LDLR–TCR interaction, PCSK9 causes TCR to be sorted into the lysosomal pathway instead of returning to the cell surface. In the lysosome, TCR is degraded by acid hydrolases, resulting in reduced TCR expression and impaired antigen recognition and signaling [122]. This process is separate from PCSK9's function in controlling MHC I levels, as it happens even without MHC I or in cells that do not express MHC I [122].
The interference of TCR recycling and signaling by PCSK9 has important implications for cancer immunotherapy, as it reduces the capacity of T cells to respond to tumor antigens and exert cytotoxic effects [137]. By inhibiting PCSK9, either genetically or pharmacologically, TCR recycling and signaling are restored, and the antitumor activity of T cells is potentiated [122]. This improves the effectiveness of ICT for cancer, including PD-1/PD-L1 blockade, which intends to revive the antitumor activity of T cells by preventing the PD-1 and PD-L1 interaction [122]. PCSK9 inhibition can also synergize with other strategies that increase the expression or function of TCR, such as interleukin-2 (IL-2), CD28 costimulation, or CAR-T-cell therapy [122,138]. Therefore, targeting PCSK9 represents a novel approach to modulate TCR expression and enhance the antitumor effectiveness of ICT.
Stimulation of CD8+ T-cell infiltration and Treg cell exclusion
Another mechanism by which inhibiting PCSK9 boosts the antitumor efficacy of anti-PD-1/PD-L1 immunotherapy involves modulating the composition and function of TIIC [19,122]. TIICs consist of various cell types that can enhance or suppress tumor growth and immunity, depending on their type, ratio, and activation state [139]. Among TIICs, CD8+ T cells and Treg cells are 2 important subsets with opposite roles in tumor immunity. CD8+ T cells are cytotoxic lymphocytes that can directly eradicate tumor cells and generate proinflammatory cytokines, including IFN-γ and tumor TNF-α [140]. Treg cells are immunosuppressive lymphocytes capable of inhibiting the activation and function of CD8+ T cells and other effector cells by generating anti-inflammatory cytokines, including IL-10 and transforming growth factor-β (TGF-β) [141]. Therefore, the equilibrium between CD8+ T cells and Treg cells in the TME is vital for determining the outcome of tumor immunity and therapy.
PCSK9 inhibition can shift the balance of TIIC to favor CD8+ T cells and against Treg cells, thereby potentiating the antitumor effectiveness of anti-PD-1/PD-L1 immunotherapy [19]. Wang et al. demonstrated that inhibiting PCSK9 enhances the infiltration of CD8+ T cells while reducing the up-regulation of Treg cells in tumor models treated with an anti-PD-1 antibody [19]. PD-1 blockade increased the infiltration of Treg and CD8+ T cells within CT26, MC38, and CRC tumor models [19]. After that, they combined the anti-PD-1 therapy with an anti-PCSK9 antibody and detected PD-1 blockade-induced Treg cells and tumor-infiltrating CD8+ T cells [19]. The results indicated that targeting PCSK9 potentiated the infiltration of CD8+ T cells and eliminated the PD-1 blockade-induced increase in Treg cells. Furthermore, Yuan et al. proved that PCSK9 treatment could reduce the expression of the cytokines IFN-γ and TNF-α, cytokines that activate TIIC in the TME, in CD8+ T cells [122]. These results indicated that PCSK9 inhibition not only modulates the quantity but also improves the quality of TIIC in the TME, suggesting that PCSK9 inhibition influences the trafficking of TIIC and regulates the cytokine profile of the TME.
Inhibition of PCSK9 emerges as a compelling strategy to augment antitumor immunity, particularly through the enhancement of CD8+ T-cell infiltration and the concomitant reduction of Treg cell populations within the TME. This synergistic dual action is pivotal for shifting the equilibrium in favor of a potent antitumor immune response. The activation of CD8+ T cells, which are instrumental in the direct targeting and elimination of neoplastic cells, alongside the suppression of immunosuppressive Treg cells, fosters a more vigorous immune reaction against cancer [142]. The conception of innovative approaches that target immune checkpoints, such as PCSK9 inhibition, is underscored for its capacity to amplify the efficacy of immunotherapeutic interventions, notably those in conjunction with anti-PD-1/PD-L1 therapies [143]. Rastin et al. [144] discussed innovative delivery systems for immunotherapeutic agents, which could potentially be applied to PCSK9 inhibitors to ensure precise and targeted delivery to the tumor site. Mashhadi et al. [145] synthesized the existing knowledge regarding PCSK9's implications in cancer prognosis and its emergent role as an immune therapy target. It suggests that inhibiting PCSK9 not only affects cholesterol metabolism but also modulates the immune response, making it a multifaceted target for cancer treatment [145]. Collectively, these insights suggest the capacity of PCSK9 inhibition to reconfigure the immunological milieu within the TME, thereby potentially enhancing the therapeutic efficacy of immunotherapies. Nonetheless, further in-depth research is imperative to elucidate the underlying mechanisms and to effectively translate these scientific discoveries into tangible clinical applications.
Combined Applications of PCSK9 Inhibitors and Anti-PD-1/PD-L1 Therapy in the Clinic
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Combining PCSK9 inhibition with anti-PD-1/PD-L1 immunotherapy has yielded promising preclinical results [146], which enhance the antitumor immune response and overcoming resistance to ICT. However, this combination strategy's clinical evidence and applications are still limited and need to be further explored and validated. This section reviews the current clinical trials evaluating the efficacy and safety of PCSK9 inhibition and anti-PD-1/PD-L1 immunotherapy in different types of cancer and discusses the potential benefits and challenges of this novel therapeutic approach.
To date, 6 relevant clinical studies have been performed (ClinicalTrials.gov, Table 3). Among them, the first enrolled study (NCT03337698) was a phase Ib/II, open-label, multicenter, randomized umbrella study launched by Smilow Cancer Hospital at Yale New Haven and 37 additional locations; this study started on 2018 January 2. This study evaluated the safety, effectiveness, and pharmacokinetics of multiple immunotherapy combination therapies in individuals with metastatic non-small cell lung cancer (NSCLC). In this study, one of the treatment arms was a combination of atezolizumab, a PD-L1 inhibitor, and evolocumab, a PCSK9 inhibitor. The main endpoint was the percentage of patients with an objective response. In addition, the first relevant study enrolled in China (NCT05128539) was an open-label phase I clinical study launched by Henan Tumor Hospital. This study evaluated the safety, tolerability, pharmacokinetics, and initial efficacy of JS002 (Ongericimab), a bioengineered humanized anti-PCSK9 monoclonal antibody, combined with JS001 (Toripalimab), a PD-1 inhibitor, in individuals with progressive cancer for whom standard therapy has failed. The primary outcome measures were adverse event (AE), serious adverse event (SAE), immune-related adverse event (irAE), dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended dose for extension (RDE). Furthermore, the first enrolled randomized controlled trial (RCT) (NCT05144529) was a randomized pilot study launched by Duke University Medical Center. This study combined evolocumab (a PCSK9 inhibitor) with nivolumab (a PD-1 inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] inhibitor) in patients with metastatic NSCLC. This study aimed to determine the safety and tolerability of consuming evolocumab with standard immunotherapy in individuals with advanced lung cancer. The primary outcome measures were DLT and changes in CD3+ T cells. By combining a PCSK9 inhibitor with an immune checkpoint inhibitor, these trials hope to achieve synergistic effects of increasing tumor immunogenicity and overcoming PD-1/PD-L1-mediated immune suppression.
Our center also initiated a multicenter, prospective, randomized controlled study (NCT06304987) to evaluate the effectiveness and safety of neoadjuvant chemoradiotherapy combined with PD-1 blockade (Sintilimab) and a PCSK9 inhibitor (Tafolecimab) for treating pMMR/MSS locally advanced rectal cancer (LARC). Fifty LARC patients whose distance from the distal border of the tumor to the anal verge was ≤10 cm were consecutively enrolled and randomized (1:1) into the control or experimental group. Patients in the control group will receive long-term radiotherapy (50 Gy/25 fractions, 2 Gy/fraction, 5 days/week), three 21-day cycles of capecitabine (850 to 1,000 mg/m2, bid, po, days 1 to 14), and three 21-day cycles of PD-1 blockade (200 mg, iv. gtt, day 8) as neoadjuvant therapy. For the experimental group, patients will receive long-term radiotherapy (50 Gy/25 fractions, 2 Gy/fraction, 5 days/week), three 21-day cycles of capecitabine (850 to 1,000 mg/m2, bid, po, days 1 to 14), three 21-day cycles of PD-1 blockade (200 mg, iv. gtt, day 8), and a PCSK9 inhibitor (600 mg, ih, week 1 and week 7) twice as neoadjuvant therapy. The primary endpoint was the complete response (CR) rate, which was defined as the rate at which patients reached clinical complete response (cCR) or pathological complete response (pCR). The secondary endpoints were major pathological response rate (MPR), objective response rate (ORR), disease-free survival (DFS), overall survival (OS), organ preservation rate (OPR), neoadjuvant rectal cancer score (NAR), and quality of life score (QoL). We hope that this strategy will improve the organ preservation rate and quality of life of LARC patients without affecting survival outcomes, and we will further explore a pathway to enhance the effectiveness of ICT for treating pMMR/MSS patients.
Summary and Outlook
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This review provides an overview of the current insights into the role of PCSK9 in cholesterol metabolism and cancer biology and discuss the potential benefits and challenges of combining PCSK9 inhibition with anti-PD-1/PD-L1 immunotherapy for cancer treatment. PCSK9 is a serine proteinase that regulates cholesterol metabolism by attaching to LDLR and directing it for lysosomal degradation [99]. PCSK9 also interacts with other membrane receptors, such as MHC I, and affects their trafficking and stability [126]. PCSK9 inhibition can lower serum cholesterol levels and suppress tumor growth by modulating tumorigenic signaling pathways, ferroptosis, and the TME [117,118,120,122]. Moreover, PCSK9 inhibition can enhance the antitumor effectiveness of anti-PD-1/PD-L1 immunotherapy by restoring MHC I recycling and antigen presentation and promoting LDLR-mediated TCR recycling and signaling [122,126]. Therefore, targeting PCSK9 represents a novel approach to modulate cholesterol metabolism and enhance the antitumor effect of ICT.
However, some limitations and challenges need to be addressed before applying this combination strategy in clinical application. First, the optimal dose, timing, and duration of PCSK9 inhibition and anti-PD-1/PD-L1 immunotherapy need to be determined based on the tumor type, phase, and molecular characteristics. Second, the safety and tolerability of PCSK9 inhibition and anti-PD-1/PD-L1 immunotherapy need to be evaluated, especially in patients with cardiovascular diseases, diabetes, or other comorbidities. Third, biomarkers and predictors of response and resistance to PCSK9 inhibition and anti-PD-1/PD-L1 immunotherapy, such as PCSK9 expression, LDLR expression, MHC I expression, the TCR repertoire, and tumor mutational burden, need to be identified and validated. Fourth, the mechanisms of interaction and synergy between PCSK9 inhibition and anti-PD-1/PD-L1 immunotherapy, such as the effects of PCSK9 inhibition on other immune cells, cytokines, and chemokines in the TME, need to be further elucidated. Fifth, the prospect of combining PCSK9 inhibition and anti-PD-1/PD-L1 immunotherapy with other therapeutic modalities, such as chemotherapy, radiotherapy, targeted therapy, or other immunotherapies, needs to be explored and optimized. Therefore, the full realization of this combined therapeutic potential awaits further preclinical and clinical validation.
In conclusion, the convergence of PCSK9 inhibition with anti-PD-1/PD-L1 immunotherapy presents a multifaceted approach to cancer treatment, offering a tapestry of benefits that extend beyond the conventional therapeutic modalities. This synergistic combination not only modulates cholesterol metabolism but also invigorates the antitumor immune response, providing a double-edged sword against cancer. The distinct advantage of PCSK9 inhibitors lies in their non-cytotoxic nature, which results in a sensibly lower incidence of adverse reactions compared to traditional chemotherapeutic agents and radiation therapies. This lower toxicity profile contributes to an improved safety margin, making it an attractive option for patients who may not tolerate other aggressive treatments. Emerging evidence highlighting the link between tumors and hyperlipidemia further underscores the potential of PCSK9 inhibitors. This correlation suggests that the metabolic anomalies associated with hyperlipidemia might be harnessed to bolster the antitumor effects of immunotherapy, offering a dual therapeutic benefit. Particularly for obese patients, this combination could address both their metabolic and oncologic challenges simultaneously. The ease of administration of PCSK9 inhibitors, typically through subcutaneous injection, enhances patient compliance and simplifies treatment regimens. This convenience, coupled with the therapeutic effectiveness, may sensibly improve the quality of life for patients undergoing cancer treatment. In summary, the fusion of PCSK9 inhibition and anti-PD-1/PD-L1 immunotherapy heralds a new era in cancer therapeutics, with the promise of a safer, more patient-friendly, and potentially more effective treatment option. As we stand on the precipice of this novel therapeutic frontier, the scientific community eagerly anticipates the forthcoming research that will undoubtedly refine and expand our understanding, paving the way for improved cancer care.
Funding
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  • National Natural Science Foundation of China (82202884)
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Article Info
doi: 10.34133/research.0488
  • Receive Date：2024-07-15
  • Online Date：2025-07-24
  • Published：2024-09-25
Article Data
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History
  • Received：2024-07-15
  • Revised：2024-08-28
  • Accepted：2024-09-09
Funding
National Natural Science Foundation of China (82202884)
Affiliations
    1Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing, China.
    2Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
    3College of Biological Sciences and Technology, Yili Normal University, Yining, China.

Corresponding:

* Address correspondence to: (Z.Z.); (H.Y.); (Z.Y.)
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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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