The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index; 4 of the 6 sources its claims cite were checked for support.
Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer
Open accessAbstract
Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer 1,2. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy 3-5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism 6-8-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.
Overview
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Written from the paper’s full text.
TL;DR
PCSK9 inhibition, via genetic deletion or clinically approved antibodies, potentiates anti-PD1 immune checkpoint therapy in murine tumors by increasing tumor-cell surface MHC I and cytotoxic T-cell infiltration, independent of cholesterol/LDLR regulation. PCSK9 physically promotes MHC I lysosomal degradation, and high tumor PCSK9 mRNA correlates with worse overall survival in TCGA cohorts.
Key findings
- PCSK9 knockout in B16F10, 4T1, MC38, and CT26 murine cancer cells attenuated tumor growth in syngeneic mice; this effect was absent in T/B/NK-deficient NCG mice and Rag1-deficient mice, and CD8+ T-cell depletion completely abolished the tumor growth delay.
- PCSK9 deficiency synergized with anti-PD1 therapy in all four tumor models; evolocumab or alirocumab plus anti-PD1 suppressed MC38 tumor growth and produced long-term survival in some mice, and evolocumab was effective in anti-PD1-resistant MC38R tumors but had no effect on PCSK9-deficient MC38 tumors.
- PCSK9 inhibition increased tumor cell surface MHC I (H2-Kb/SIINFEKL, H2b, H2d, HLA-A2), intratumoral CD8+ CTLs, CD4+ Th cells, γδT cells, NK cells, CTL/Treg ratios, IFNγ+ and GZMB+ CTLs, and TCR counts/diversity, without significant increases in Tregs or exhaustion markers.
- Mechanistically, PCSK9 bound H2-K1 via its M2 domain and H2-K1 aa68–70, promoting MHC I relocation to the lysosome and degradation; LDLR knockdown did not affect MHC I surface levels or the growth suppression caused by PCSK9 deficiency, and high PCSK9 mRNA was associated with worse overall survival in 9 TCGA cancer cohorts.
Methods
- Murine cancer cell lines (B16F10, 4T1, MC38, CT26) and human MDA-MB-231 cells were modified with CRISPR/Cas9 PCSK9 knockout, LDLR knockdown/knockout, or H2-K1 knockout/overexpression; in vitro growth and soft agar assays were used, and in vivo experiments used syngeneic C57BL/6J or Balb/c mice, NCG mice, Rag1−/− mice, LDLR−/− mice on high-fat diet, and OT-1 transgenic mice.
- Tumor growth delay, survival, in vivo competition, and re-challenge experiments were performed; treatments included anti-PD1 (clone RMP1–14), evolocumab, alirocumab, isotype controls, and antibody-mediated depletion of CD4+, CD8+, or NK cells.
- Analyses included flow cytometry, immunofluorescence, qRT-PCR, TCR sequencing, co-immunoprecipitation, cell fractionation, cycloheximide chase, and bafilomycin treatment; human correlations used GENT for PCSK9/CD8A and TCGA/cBioPortal for PCSK9 mRNA and overall survival, with two-way ANOVA, log-rank tests, and unpaired two-sided t tests.
Limitations
- The paper states that no randomization or blinding was used in the tumor growth delay experiments.
- The paper has no explicit limitations section; evident from the text, the efficacy and mechanistic findings are primarily preclinical in murine tumor models and cell lines, and the human evidence is correlative (GENT/TCGA), not from a clinical trial of PCSK9 inhibition plus checkpoint blockade.
- Also evident, several mechanistic domain-mapping experiments rely on overexpression or deletion mutants in 293T/B16F10 cells, which may not fully reflect endogenous PCSK9–MHC I interactions.
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Claims the paper makes
78 Own result · 19 Own method · 19 Own interpretation · 2 Partly supported · 2 No full text of the sources · 1 Supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“deletions of the other two domains (M1 & M3) and the aa367–386 domain, which was involved in LDLR binding34, in the catalytic region, also showed reduced H2-K1 binding”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
What the sources say
- Supportedcites [34] Duff, C. J. et al. Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor. Biochem. J. 419, 577–584 (2009). source
The citation is attached to the LDLR-binding description, not the claim about reduced H2-K1 binding. In Results (page unavailable), the paper places an overlapping PCSK9 region, aa 365–384, in the catalytic domain near Asp374 and describes it as critical to interaction with LDLR; antibodies against that region reduced PCSK9–LDLR binding. The paper gives slightly different residue boundaries from aa 367–386. (LLM, conf=0.86)
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In the paper
“Previous studies have demonstrated that the amount of active T-cells is positively correlated with the success of immune checkpoint blockade therapy36,37”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Discussion
What the sources say
- Partly supportedcites [36] Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003). sourceExperimental — accuracy not yet measured
The ‘Intratumoral T Cells and Clinical Outcome’ section reports that patients with intratumoral T cells had longer progression-free and overall survival, and the discussion describes evidence that those T cells were activated. The paper does not examine immune checkpoint blockade or show that the amount of active T cells predicts its success; its finding concerns T-cell presence and outcomes in ovarian cancer. (LLM, conf=0.86)
- Partly supportedcites [37] Carstens, J. L. et al. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat. Commun. 8, 15095 (2017). sourceExperimental — accuracy not yet measured
The Abstract links endogenous antitumour T cells to the efficacy of therapies combined with checkpoint blockade. But it does not report a positive correlation between the amount of active T cells and checkpoint-blockade success. The Discussion states that T-cell functional status was not measured; page numbers are unavailable in our copy. (LLM, conf=0.86)
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In the paper
“anti-PD1 therapy was ineffective, as reported before29”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
What the sources say
- Partly supportedcites [29] Kim, K. et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl Acad. Sci. USA 111, 11774–11779 (2014). sourceExperimental — accuracy not yet measured
The Effects of Immune Checkpoint Blockade section describes 4T1 tumors as resistant to immunotherapy, and the Discussion says combined anti-PD-1/anti-CTLA-4 treatment generally could not cure them. The copy does not explicitly report the outcome of anti-PD-1 alone in 4T1 mice; moreover, 3 of 10 mice had complete primary-tumor regression with the combination, so “ineffective” needs qualification. (LLM, conf=0.79)
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“It also enhanced the efficacy of anti-PD1 immune checkpoint therapy significantly.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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“clinically approved PCSK9-neutralizing antibodies could synergize with anti-PD1 therapy in suppressing tumor growth in murine tumor models”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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In the paper
“PCSK9 inhibition, either through genetic deletion or PCSK9 antibodies, caused a significant increase in tumor cell surface major histocompatibility protein class I (MHC I) expression”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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“Deletion of the PCSK9 gene in murine cancer cells significantly attenuated or prevented their growth in mice”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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“in a cytotoxic T-cell-dependent manner”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Abstract
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“depletion of CD4+ T cells or NK cells only had marginal effects”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“patients with high tumor PCSK9 mRNA expression had worse overall survival than those with low expression in 9 different TCGA (The Cancer Genome Atlas) patient cohorts”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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In the paper
“PCSK9 knockout (PCSK9KO) did not alter the morphology or the in vitro growth rates of tumor cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 deficiency and tumor growth rate
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“both anti-PD1 and anti-PCSK9 antibodies could boost the numbers of CTLs inside the tumor”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“Our results indicated that PCSK9 more susceptible to killing by CTLs”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“re-introduction of the wild type PCSK9 abolished the tumor growth delay while that of PCSK9ΔM2 had no effect”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“H2-K1 expression could significantly attenuate tumor growth alone or in combination with anti-PD1”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“when the cells were exposed to bafilomycin to inhibit lysosome function, the levels of HLA-ABC increased significantly in control cells but did not change much in PCSK9KO cells”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“Evolocumab treatment was effective either alone or in combination with anti-PD1 treatment for MC38R tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
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“In contrast, in the membrane fraction, PCSK9OE reduced the relative abundance of the H2-K1 protein while PCSK9 knockout increased it”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“CD8+ cells staying mostly in the periphery in control tumors (Extended Data Fig. 6b, top panels) but moving into tumor cell-rich areas in the PCSK9-deficient B16F10 tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“In the lysosome fraction, PCSK9 OE caused an increase in H2-K1 protein while PCSK9KO induced a decrease”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
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“their efficacies were enhanced significantly when combined with an anti-PD1 antibody, with long-term survival of some host mice”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 inhibition and immunotherapy
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“It suggests that PCSK9 neutralization may promote intratumoral T cell infiltration and thus render tumors more responsive to immune checkpoint therapy”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Discussion
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“These results suggest that both the number and diversity of mature T-cells were significantly elevated in PCSK9-deficient tumors”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and lymphocyte infiltration
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“The finding that PCSK9 plays important roles in regulating cell surface MHC I levels (see Extended Data Fig. 10 for a summary schema) and thus influences intratumoral immune infiltration is novel mechanistically”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Discussion
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“The analyses were repeated twice with biologically independent samples with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“All animal experiments conducted in this study were approved by Duke University Institutional Animal Use and Care Committee (IACUC)”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Tumor growth in mice.
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“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“Their identities were verified by the STR method”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Cell lines.
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“All cell lines were subjected to mycoplasma test periodically”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Cell lines.
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“expression of target protein (PCSK9) in infected cells were detected by western blot to verify the knockdown”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > CRISPR/Cas9-mediated gene knockout.
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“At least 5 mice per treatment group were included”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Tumor growth in mice.
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“Original uncropped images highlighting the cropped areas were shown in Supplementary Data Fig. 1”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Western blot analysis.
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“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“The experiments were completed twice with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“Shown were representative results from analyses of 4 sets of biologically independent samples.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“The analyses were done twice.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“The analyses were repeated twice with biologically independent samples with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
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“Two independent experiments were carried out”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Soft agar colony formation assay.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analyses were repeated twice with biologically independent samples with similar results.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the absence of PCSK9, either because of genetic deletion or antibody neutralization, MHC I levels on the surface remains high and is thus able to present tumor-specific peptic antigens more efficiently to T cells (right panel).”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The analysis was done once.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Analysis was done twice with biologically independent samples.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
plainn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No randomization or blinding was used in our tumor growth delay experiments”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Methods > Tumor growth in mice.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Findings from murine tumor models and cell lines will translate to human cancer patients.
“provide compelling rationales for conducting future clinical trials in human cancer patients”
The paper relies on this without support.
Combining PCSK9 inhibitors with immune checkpoint blockade will not add side effects.
“Given the well-known safety profiles of the anti-PCSK9 antibodies, PCSK9 inhibitors may enhance immune checkpoint blockade therapy without additional side effects.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > PCSK9 and MHC I regulation
“Furthermore, LDLR knockout did not affect the up-regulation of surface MHC I expression induced by PCSK9 deficiency (Extended Data Fig. 8j).”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
“j. Flow cytometry analysis of MHC I expression in tumors formed from tdTomato-labeled LDLRKD (n=6) and LDLRKD/PCSK9KO cells (n=4).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
“b-c. Tumor growth delay (b) and Kaplan-Meier survival curve (c) of tumor-bearing C57BL/6 mice implanted with vector control or H2-K1 over-expression B16F10 cells.”
§ PCSK9 inhibition potentiates cancer immune checkpoint therapy > Extended Data
“d-e. Tumor growth delay (d) and Kaplan-Meier survival curves (c) in mice injected with vector control, H2-K1 KD, PCSK9 KO, or H2-K1KD/PCSK9KO B16F10 cells.”
Citations
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Cited by
Sorted by citations
Items 101–200 of 490
Lagunas‐Rangel, F. A. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1579054 · Cited by 39
Xu, N., Zhu, Y., Han, Y., Liu, Q., Tong, L., Li, Y., Chen, Z., Shao, S., He, W., Li, M., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01347-1 · Cited by 47
Self-citationLan, P., Chen, H., Guo, Y., Li, Y., Zheng, Y. F., Zhang, Y., Li, M., Guo, Z., & Liu, Z. (2022) · Nano Letters · doi:10.1021/acs.nanolett.2c00899 · Cited by 40
PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity
Gu, Y. J., Lin, X., Dong, Y., Wood, G. A., Seidah, N. G., Werstuck, G. H., Major, P. P., Bonert, M., Kapoor, A., & Tang, D. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02584-y · Cited by 39
“Abbreviations CI: Confidence interval; DEGs: Differentially-expressed genes; EV: Empty vector; GOF: Gain-of-function; GSEA: Gene set enrichment analysis; HR: Hazard ratio; ICB: Immune checkpoint blockade; LDLR: Low-density lipoprotein receptor; LOF: Loss-of-function; NW: Network; PR: Precision-recall; ROC AUC : Receiv…”
BackgroundInfluentialLu, Z. F., Chen, J., Yu, P., Atherton, M. J., Gui, J., Tomar, V. S., Middleton, J. D., Sullivan, N. T., Singhal, S. K., George, S. S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34428-w · Cited by 39
The immunosuppressive landscape in tumor microenvironment
Liu, W., Zhou, H., Lai, W., Hu, C., Xu, R., Gu, P., Luo, M., Zhang, R., & Li, G. (2024) · Immunologic Research · doi:10.1007/s12026-024-09483-8 · Cited by 44
“Besides, other inhibitory immune molecules expressed on tumor cells have also been reported, including Galectin-9 [35], HVEM [36], PCSK9 [37], ERMAP [38], and MEF2D [39].”
Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy
Liu, P., Lin, C., Liu, Z., Zhu, C., Lin, Z., Xu, D., Chen, J., Huang, Q., Li, C., Hou, L., et al. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04365-4 · Cited by 38
“To investigate the ability of immunogenic ALG3-deficient cells to attract lymphocyte infiltration on tumor sites, we proposed to analyze tumor infiltrating lymphocytes (TIL) in control and ALG3-deficient B16 tumors by immunofluorescence staining and flow cytometry as described previously [36].”
BackgroundMethodSelf-citationChasing LDL cholesterol to the bottom — PCSK9 in perspective
Libby, P., & Tokgözoğlu, L. S. (2022) · Nature Cardiovascular Research · doi:10.1038/s44161-022-00085-x · Cited by 41
Kang, K., Wu, Y., Yao, Z., & Lü, Y. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216239 · Cited by 39
Dutka, M., Zimmer, K., Ćwiertnia, M., Ilczak, T. P., & Bobiński, R. (2024) · Heart Failure Reviews · doi:10.1007/s10741-024-10409-7 · Cited by 46
Zou, Y., Chen, Z., Zhang, X., Yu, J., Xu, H., Cui, J., Li, Y., Niu, Y., Zhou, C., Xia, J., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.894789 · Cited by 36
“Additionally, the combination of anti-programmed cell death protein 1 monoclonal antibody and Evolocumab has been shown to promote infiltration of cytotoxic T cells and inhibit tumor growth (15).”
BackgroundTargeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC
Zhao, X., Guo, B., Sun, W., Yu, J., & Cui, L. (2023) · Advanced Science · doi:10.1002/advs.202206878 · Cited by 36
The emerging landscape of peptide-based inhibitors of PCSK9
Tombling, B. J., Zhang, Y., Huang, Y., Craik, D. J., & Wang, C. K. L. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.06.903 · Cited by 34
Immunometabolism in the tumor microenvironment and its related research progress
Zhang, Z., Hu, Y., Chen, Y., Chen, Z., Zhu, Y., Chen, M., Xia, J., Sun, Y., & Xu, W. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1024789 · Cited by 35
Peng, L., Zhou, L., Li, H., Zhang, X., Su, L., Wang, K., Yang, M., Ma, X., Zhang, D., Xiang, S., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114003 · Cited by 34
Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis
Alannan, M., Fatrouni, H., Trézéguet, V., Dittrich-Domergue, F., Moreau, P., Siegfried, G., Liet, B., Khatib, A., Grosset, C. F., Badran, B. M., et al. (2022) · Cells · doi:10.3390/cells12010062 · Cited by 35
“[27] demonstrated that the blockade of PCSK9 can boost the immunotherapeutic efficacy of the anti-programmed death 1 (PD-1) approach.”
BackgroundPCSK9 regulates the efficacy of immune checkpoint therapy in lung cancer
Gao, X., Yi, L., Jiang, C., Li, S., Wang, X., Yang, B. T., Li, W., Che, N., Wang, J., Zhang, H., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1142428 · Cited by 37
“To conclude, our study demonstrated that high PCSK9 expression in baseline tumor tissue could be a deleterious factor in advanced NSCLC patients receiving ICIs with poorer efficacy.”
BackgroundResultInfluentialLi, Y., Chen, Y., Zhao, C., Yang, Y., Zhang, M., Cheng, H., Li, Q., & Wang, M. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155532 · Cited by 33
Etiology and Management of Dyslipidemia in Patients With Cancer
de Jesus, M., Mohammed, T. J., Singh, M., Tiu, J. G., & Kim, A. S. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.892335 · Cited by 32
“Although the data supporting the use of PCSK9 inhibitors primarily as antilipidemic agent in patients with cancer is limited, preliminary data suggests that it may potentially assist anti-cancer therapy by boosting the effect of immunotherapy by upregulating the MHC-I expression and promoting intratumoral T-cell infil…”
BackgroundLoss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons
Liu, Y., Hu, L., Wu, Z., Yuan, K., Hong, G., Lian, Z., Feng, J., Li, N., Li, D., Wong, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39943-y · Cited by 32
“Moreover, Phf8-KO tumor cells had a marked growth disadvantage over wild-type cells in an in vivo competitive assay 26 (Supplementary Fig.”
Chen, Z., Shao, W., Li, Y., Zhang, X., Geng, Y., Ma, X., Tao, B., Ma, Y., Yi, C., Zhang, B., et al. (2024) · Metabolism · doi:10.1016/j.metabol.2023.155774 · Cited by 36
Zhang, W., Chen, L., Liu, J., Chen, B., Shi, H., Chen, H., Qi, H., Wu, Z., Mao, X., Wang, X., et al. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03023-w · Cited by 30
“Research has shown that inhibiting cholesterol potentially improves immune checkpoint therapy for cancer [34].”
BackgroundZhong, P., Nakata, K., Oyama, K., Higashijima, N., Sagara, A., Date, S., Luo, H., Hayashi, M., Kubo, A., Wu, C., et al. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03060-5 · Cited by 36
“Although these results seem to conflict with ours, the mechanism is independent of cholesterol regulation, relying on direct interaction with MHC-I and reducing lysosomal degradation [11].”
BackgroundWenta, T., Nastały, P., Lipińska, B., & Manninen, A. (2024) · Matrix Biology · doi:10.1016/j.matbio.2024.10.007 · Cited by 33
Epigenetic modifications and emerging therapeutic targets in cardiovascular aging and diseases
Qiu, Y., Xu, Q., Xie, P., He, C., Li, Q., Yao, X., Mao, Y. H., Wu, X., & Zhang, T. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107546 · Cited by 33
Targeting PCSK9 reduces cancer cell stemness and enhances antitumor immunity in head and neck cancer
Yang, Q., Wang, S., Liu, Y., Song, A., Wu, Z., Wan, S., Li, H., & Sun, Z. (2023) · iScience · doi:10.1016/j.isci.2023.106916 · Cited by 31
“As a key regulator of cholesterol metabolism, PCSK9 has also been reported to play an important role in regulating CD8 T antitumor immunity by reducing MHC-I expression in tumor cells or mediating T cell receptor degradation.(20,21) Consistently, we found that PCSK9 expression was upregulated and positively associated…”
BackgroundInfluentialLao, M., Zhang, X., Li, Z., Sun, K., Yang, H., Wang, S., He, L., Chen, Y., Zhang, H., Shi, J., et al. (2025) · 癌症：英文版 · doi:10.1002/cac2.70038 · Cited by 31
“Liu X et al. demonstrated that PCSK9 promoted lysosome-mediated degradation of MHC-I in tumor cells [33].”
Suh, J. M., Son, Y., Yoo, J.-Y., Goh, Y., Seidah, N. G., Lee, S., & Bae, Y. S. (2021) · Neoplasia · doi:10.1016/j.neo.2021.07.007 · Cited by 28
Chen, Y., Jin, Y., Hu, X., & Chen, M. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-021-03895-x · Cited by 30
“High expression of MHC class I enhances T cell infiltration into tumors in melanoma and other cancers (Liu et al. 2020; Desbois et al. 2020; Al-Batran et al. 2005; Wang et al. 2020).”
BackgroundCirculating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancers
Chong, E. W., Joncas, F., Seidah, N. G., Calon, F., Diorio, C., & Gangloff, A. (2022) · BMC Cancer · doi:10.1186/s12885-022-10120-6 · Cited by 30
“Inhibition of PCSK9 not only protects LDLR but also MHC-I from PCSK9-induced degradation [34].”
BackgroundZhang, Q., Xiu, B., Zhang, L.-Y., Chen, M., Chi, W., Li, L., Guo, R., Xue, J., Yang, B., Huang, X., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-004666 · Cited by 31
Toxicities associated with immune checkpoint inhibitors: a systematic study
Kong, X., Chen, L., Su, Z., Sullivan, R. J., Blum, S. M., Qi, Z., Liu, Y., Huo, Y., Fang, Y., Zhang, L., et al. (2023) · International Journal of Surgery · doi:10.1097/js9.0000000000000368 · Cited by 31
Xie, J., Zhuang, Z., Gou, S., Zhang, Q., Wang, X., Lan, T., Lian, M., Li, N., Liang, Y., Ouyang, Z., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad687 · Cited by 30
Yang, K., Zhu, J., Luo, H., Yu, S., & Wang, L. (2021) · International Journal of Immunopathology and Pharmacology · doi:10.1177/20587384211038345 · Cited by 28
“Evolocumab has been widely used in clinical settings, and PCSK9 inhibitors have been reported to enhance immune checkpoint blockade therapy without additional side effects.(45) Further preclinical and clinical trials are needed to verify the efficacy and safety of PCSK9 inhibitors on tumor incidence and progression.”
BackgroundInfluentialXu, W., Hu, M., Lu, X., Lao, Y., Ma, N., Wang, Y., Li, J., Chen, X., Liu, S., Liu, J., et al. (2024) · International Journal of Biological Sciences · doi:10.7150/ijbs.93668 · Cited by 27
Self-citationInhibition of PCSK9: A Promising Enhancer for Anti-PD-1/PD-L1 Immunotherapy
Sun, S., Ma, J., Zuo, T., Shi, J., Sun, L., Meng, C., Shu, W., Yang, Z., Yao, H., & Zhang, Z. (2024) · Research · doi:10.34133/research.0488 · Cited by 28
Lipid metabolism and tumor immunotherapy
Wang, Y., Guo, Z., Danbala, I. A., Chen, S., Ren, Y., & Cai, H. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1187989 · Cited by 27
Tumor-intrinsic metabolic reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment
Laubach, K., Turan, T., Mathew, R. S., Wilsbacher, J. L., Engelhardt, J., & Samayoa, J. A. (2023) · Cancer Drug Resistance · doi:10.20517/cdr.2023.60 · Cited by 27
MiR-337-3p lowers serum LDL-C level through targeting PCSK9 in hyperlipidemic mice
Xu, X., Dong, Y., Ma, N., Kong, W., Yu, C., Gong, L., Chen, J., & Ren, J. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154768 · Cited by 24
PCSK9, a novel immune and ferroptosis related gene in abdominal aortic aneurysm neck
Zhuang, J., Zhu, H., Cheng, Z., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-33287-9 · Cited by 25
Interorgan communication with the liver: novel mechanisms and therapeutic targets
Zhao, J., Zhang, X., Li, Y., Yu, J., Chen, Z., Niu, Y., Ran, S., Wang, S., Ye, W., Luo, Z., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1314123 · Cited by 31
“Inhibition of PCSK9 with small molecule compounds or monoclonal antibodies upregulates cell surface MHC I and enhances tumoral in fi ltrated lymphocytes (73, 74).”
BackgroundFang, S., Zheng, L., Shu, G., Xiaoxiao, C., Guo, X., Ding, Y., Yang, W., Chen, J., Zhao, Z., Tu, J., et al. (2024) · ACS Nano · doi:10.1021/acsnano.3c11775 · Cited by 24
Sun, H., Meng, W., Zhu, J., & Wang, L. (2022) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-022-02200-y · Cited by 24
Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer
Lin, P., Lin, Y., Xu, C., Zhao, X., & Cui, L. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70403 · Cited by 25
Ito, M., Hiwasa, T., Oshima, Y., Yajima, S., Suzuki, T., Nanami, T., Sumazaki, M., Shiratori, F., Funahashi, K., Li, S., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.708039 · Cited by 23
“It has been suggested that controlling serum PCSK9 level as a low titer contributes to the suppression of cancer development and improving the prognosis of cancer (21).”
BackgroundInfluentialNie, R., Chen, G., Wang, Y., et al. (2021) · Journal of Immunotherapy · doi:10.1097/cji.0000000000000389 · Cited by 23
Sun, C., Zhu, G., Shen, C., Huang, S., Li, R., Li, J., Ma, Z., & Wang, Z. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1134063 · Cited by 22
Regulating Cholesterol in Tumorigenesis: A Novel Paradigm for Tumor Nanotherapeutics
Wu, H., Wu, X., Zhao, M., Yan, J., Li, C., Zhang, Z., Tang, S., Wang, R., & Fei, W. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s439828 · Cited by 26
“65 Thus, regulating cholesterol metabolism is an effective strategy for tumor immunotherapy.”
BackgroundSelf-citationTargeting PCSK9 to upregulate MHC-II on the surface of tumor cells in tumor immunotherapy
Wang, H., Zhang, X., Zhang, Y., Shi, T., Zhang, Y., Song, X., Liu, B., Wang, Y., & Wei, J. (2024) · BMC Cancer · doi:10.1186/s12885-024-12148-2 · Cited by 24
“Inhibiting PCSK9 caused a significant increase in tumor cell surface MHC-I expression, which promoted robust intra-tumoral infiltration of cytotoxic T-cells [16].”
BackgroundShen, L., Yang, Z., Zhong, Y., Bi, Y., Yu, J., Lu, Q., Su, Y., Chen, X., Zhao, Z., Shu, G., et al. (2024) · Advanced Science · doi:10.1002/advs.202406975 · Cited by 23
Cholesterol metabolism in tumor immunity: Mechanisms and therapeutic opportunities for cancer
Guo, X., Zhu, B., Li, J., Guo, P., Niu, Y., Shi, J., Yokoyama, W., Huang, Q., & Shao, D. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116802 · Cited by 23
Self-citationThe Role of Cholesterol Metabolism and Its Regulation in Tumor Development
Wu, Y., Song, W., Su, M., He, J., Hu, R., & Zhao, Y. (2025) · Cancer Medicine · doi:10.1002/cam4.70783 · Cited by 23
“Gene knockout or PCSK9 antibody inhibition increases the expression of MHC-I proteins on the tumor cell surface, promoting strong infiltration of cytotoxic T cells within tumors and enhancing the efficacy of anti-PD1 therapies [208].”
Fruchart‐Gaillard, C., Ouadda, A. B. D., Ciccone, L., Girard, E., Mikaeeli, S., Evagelidis, A., Dévéhat, M. L., Susan‐Resiga, D., Lajeunesse, E. C., Nozach, H., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101662 · Cited by 22
“Very recently, PCSK9 was shown to induce the lysosomal degradation of the type-I membrane-bound major histocompatibility complex-I (MHC-I), via an interaction with the M2 module of the CHRD, independently from the LDLR [31].”
BackgroundInfluentialMontero‐Calle, A., López‐Janeiro, Á., Mendes, M. L., Pérez-Hernández, D., Echevarría, I., Ruz‐Caracuel, I., Heredia-Soto, V., Mendiola, M., Hardisson, D., Argüeso, P., et al. (2023) · Cellular Oncology · doi:10.1007/s13402-023-00778-w · Cited by 22
Zheng, X., Luo, Y., Xiong, Y., Liu, X., Zeng, C., Lu, X., Wang, X., Cheng, Y., Wang, S., Lan, H., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007678 · Cited by 23
Self-citationMicroenvironmental regulation of tumour immunity and response to immunotherapy
Kockx, M. M., McCleland, M. L., & Koeppen, H. (2021) · The Journal of Pathology · doi:10.1002/path.5681 · Cited by 23
“Interestingly, the proprotein convertase subtilisin/kexin type 9 (PCSK9), independent of its role in cholesterol metabolism, can function to downregulate MHC-I by disrupting MHC-I recycling to the cell surface [73].”
BackgroundImmune Checkpoint Inhibitors and Cardiovascular Adverse Events
Perna, M. L. D., Rigamonti, E., Zannoni, R., Espeli, V. G., & Moschovitis, G. (2025) · ESC Heart Failure · doi:10.1002/ehf2.15281 · Cited by 27
Lipid metabolism in tumor-infiltrating T cells: mechanisms and applications
Ke, X., Zou, M.-W., & Xu, C. (2022) · Life Metabolism · doi:10.1093/lifemeta/loac038 · Cited by 21
Song, C., Zhang, X., Cao, Z., Wei, Z., Zhou, M., Wang, Y., Han, S., Cai, Y., & Han, W. (2023) · Chemical Engineering Journal · doi:10.1016/j.cej.2023.142160 · Cited by 21
Kounatidis, D. C., Tentolouris, N., Vallianou, N. G., Mourouzis, I. S., Karampela, Ι., Stratigou, T., Rebelos, E., Kouveletsou, M., Stamatopoulos, V., Tsaroucha, E., et al. (2024) · Metabolites · doi:10.3390/metabo14070388 · Cited by 23
“Specifically, reducing PCSK9 levels may result in heightened expression of MHC-I on tumor cell surfaces [155] and augmentation of CD8+ T cell infiltration within tumors [156].”
BackgroundGuo, H., Zhou, C. X., Zheng, M., Zhang, J., Wu, H., He, Q., Ding, L., & Yang, B. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107084 · Cited by 23
RORγ Bridges Cancer-Driven Lipid Dysmetabolism and Myeloid Immunosuppression
Bleve, A., Incerti, M., Consonni, F. M., Garlatti, V., Ballerini, G., Pandolfo, C., Monari, M., Serio, S., Pistillo, D., Sironi, M., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0199 · Cited by 24
Zhang, H., Mu, Q., Jiang, Y., Zhao, X., Jia, X., Wang, K., Li, X., & Sun, D. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06889-2 · Cited by 26
“Studies show that inhibiting PCSK9 activity can enhance the efficacy of immunotherapy [37].”
Xie, M., Yu, X., Chu, X., Xie, H., Zhou, J., Zhao, J., & Su, C. (2021) · Thoracic Cancer · doi:10.1111/1759-7714.14259 · Cited by 21
“found that the knockdown of PCSK9 could significantly delay the growth of tumors in the same strain of mice, and enhance the therapeutic effect of ICIs.(16) Another team found a similar phenomenon but a different mechanism in MC38 and B16 tumors, which also confirms the role of PCSK9 in tumors.”
BackgroundInfluentialVos, W. G., Lutgens, E., & Seijkens, T. T. P. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005611 · Cited by 20
Jin, W., Yu, J., Su, Y., Lin, H., Liu, T., Chen, J., Ge, C., Zhao, F., Geng, Q., Mao, L., et al. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.81415 · Cited by 20
“Recently, PCSK9 was found to promote tumor progression by regulating apoptosis, metastasis, and tumor immunity via lysosomal degradation of MHC Class I molecules [26,29,50,51].”
BackgroundShu, Z., Fan, M., Tu, B., Tang, Z., Wang, H., Li, H., Li, H., Yuan, M., Bai, J., Huo, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42508-8 · Cited by 20
“Recent studies uncovered more biological functions of PCSK9, including vascular in fl ammation, viral infections, or immune checkpoint modulation in cancer 36,39 .”
Self-citationLauridsen, A. R., Skorda, A., Winther, N. I., Bay, M. L., & Kallunki, T. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03172-y · Cited by 23
“…studies on PCSK9 inhibition for example as a combinatory treatment with immune checkpoint inhibition in murine 4T1 mammary cancer cell xenografts [130] and in targeting the OVCAR3 HGSC ovarian cancer cells [131] exist, generally studies with PCSK9 inhibition in cancer contain controversiali-ties…”
BackgroundThe year in cardiovascular medicine 2021: dyslipidaemia
Tokgözoğlu, L. S., Orringer, C. E., Ginsberg, H. N., & Catapano, A. L. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab875 · Cited by 22
Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease
Suur, B. E., Chemaly, M., Liljeqvist, M. L., Djordjevic, D., Stenemo, M., Bergman, O., Karlöf, E., Lengquist, M., Odeberg, J., Hurt‐Camejo, E., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.988561 · Cited by 21
“Reports that PCSK9 is not only involved in the degradation of LDLr, but also MHCI (Liu et al., 2020) and CD36 (Demers et al., 2015)molecules, could help to functionally explain our observations.”
BackgroundChan, A., Torelli, S., Cheng, E., Batchelder, R., Waliany, S., Neal, J. W., Witteles, R. M., Nguyen, P. K. P., Cheng, P. P., & Zhu, H. (2023) · Current Treatment Options in Cardiovascular Medicine · doi:10.1007/s11936-023-01024-0 · Cited by 19
“Similar to statins, recent studies have found that adjuvant PCSK9 use with ICIs, leading to enhanced intratumoral cytotoxic T cell infiltration, antigen presentation, and expression of co-inhibitory checkpoint molecules [142–144].”
ResultAberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response
Tan, L., Yin, T., Xiang, H., Wang, L., Mudgal, P., Chen, J., Ding, Y., Wang, G., Lim, B. J. W., Huang, Y., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52902-5 · Cited by 25
Statin therapy: a potential adjuvant to immunotherapies in hepatocellular carcinoma
Wang, J., Liu, C., Hu, R., Wu, L., & Li, C. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1324140 · Cited by 19
Self-citationZhan, Y., Tian, F., Fan, W., Li, X., Wang, X., Zhang, H., Hong, X., Wang, X., Cai, L., Song, Y., et al. (2024) · Advanced Science · doi:10.1002/advs.202414100 · Cited by 20
A Forgotten Corner in Cancer Immunotherapy: The Role of Lipids
Yu, Y., Gao, L., Wang, Y., Xu, B., Maswikiti, E. P., Li, H., Peng, Z., Tao, P., Xiang, L., Gu, B., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.751086 · Cited by 18
Ye, P., Jiang, X., Qian, W., et al. (2023) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-023-07458-9 · Cited by 18
“…of LDLC, but PCSK9, independent of LDLR, could induce vascular inflammation and increase the severity of cardiovascular disease via affecting chemokine receptor expression, ROS production, initiating mitochondrial DNA damage, activating NLRP3 inflammasome signaling and inducing pyroptosis [7–9].”
Wang, Q., Chen, Z., Lü, X., Lin, H., Feng, H., Weng, N., Chen, L., Liu, M., Li, L., Huang, L., et al. (2025) · Advanced Science · doi:10.1002/advs.202501623 · Cited by 19
Cathepsins: emerging targets in the tumor ecosystem to overcome cancers
Fujii, Y., Asadi, Z., & Mehla, K. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.04.001 · Cited by 21
Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment
Du, Y., Cai, Z.-R., Duan, X.-T., Li, X., Yue, T., Tian, T., Li, J.-J., & Ju, H. (2026) · Cellular and Molecular Immunology · doi:10.1038/s41423-026-01411-0 · Cited by 24
“Instead, PCSK9 restricts tumor immunity via nonmetabolic interactions, speci fi cally by targeting MHC-I for lysosomal degradation [168].”
Orchestral role of lipid metabolic reprogramming in T-cell malignancy
Mehta, A., Ratre, Y. K., Soni, V. K., Shukla, D., Sonkar, S. C., Kumar, A., & Vishvakarma, N. K. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1122789 · Cited by 18
Wang, T., Dong, Y., Yao, L., Lü, F., Wen, C., Wan, Z., Fan, L., Li, Z., Bu, T., Wei, M., et al. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.02.002 · Cited by 17
Yang, L., Pan, M., Hu, H., Liu, F., Jiang, M., Ning, S., Chen, X., Zhang, Z., Yu, X., & Xu, L. (2025) · Small · doi:10.1002/smll.202501076 · Cited by 22
Wang, Y., Chai, Y., Liu, Y., Liu, X., Zhang, Y., Yang, Z. F., Yin, S., Luo, J., Li, Z., Gu, Y., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.07.013 · Cited by 19
Self-citationImmune Checkpoint Inhibitor Therapy in Neuroendocrine Tumors
Gubbi, S., Vijayvergia, N., Yu, J. Q., Kłubo-Gwieździńska, J., & Koch, C. A. (2022) · Hormone and Metabolic Research · doi:10.1055/a-1908-7790 · Cited by 16
Essalmani, R., Andréo, U., Evagelidis, A., Dévéhat, M. L., Ramos, O. H. P., Fruchart‐Gaillard, C., Susan‐Resiga, D., Cohen, É. A., & Seidah, N. G. (2023) · Viruses · doi:10.3390/v15020360 · Cited by 17
The significance of targeting lysosomes in cancer immunotherapy
Xu, Y., Shao, B., & Zhang, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1308070 · Cited by 21
“Li et al. also found that PCSK9 physically binds to MHC I and promotes its degradation in lysosomes, thereby reducing its recycling and reutilization on the cell surface, and con fi rmed that the degradation of MHC-I by PCSK9 occurs via the lysosomal pathway using drug intervention experiments (90).”
MethodEmerging Targets and Therapeutics in Immuno-Oncology: Insights from Landscape Analysis
Iyer, K. A., Ivanov, J. M., Tenchov, R., Ralhan, K., Rodríguez, Y., Sasso, J. M., Scott, S. A., & Zhou, Q. A. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00568 · Cited by 20
The multifaceted role of PCSK9 in cancer pathogenesis, tumor immunity, and immunotherapy
Hsu, C., Abdulraheem, M. N., Mustafa, M. A., Omar, T. M., Balto, F., Grillo, I. J. P., Khudair, T. T., Ubaid, M., & Ali, M. S. (2024) · Medical Oncology · doi:10.1007/s12032-024-02435-0 · Cited by 18
“Paradoxically, PCSK9 facilitates the migration and eventual degradation of MHC I within lysosomes [169].”
InfluentialLipid-lowering drugs and cancer: an updated perspective
Alizadehasl, A., Alavi, M. S., Boudagh, S., Alavi, M. S., Mohebi, S., Aliabadi, L., Akbarian, M., Ahmadi, P., Mannarino, M. R., & Sahebkar, A. (2023) · Pharmacological Reports · doi:10.1007/s43440-023-00553-6 · Cited by 15
Aptamers combined with immune checkpoints for cancer detection and targeted therapy: A review
Li, Y., Liu, W., Xu, H., Zhou, Y., Xie, W., Guo, Y., Liao, Z., Jiang, X., Liu, J., & Ren, C. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.130032 · Cited by 16
PCSK9 in T-cell function and the immune response
Wang, Y., Fang, X., Liu, J., Lv, X., Lu, K., Lu, Y., & Jiang, Y. (2024) · Biomarker Research · doi:10.1186/s40364-024-00712-8 · Cited by 17
“They found that the inhibition of PCSK9 enhanced the tumor response to PD-1 inhibitors by promoting massive infiltration of CTLs within the tumor through a mechanism independent of the cholesterol regulatory function of PCSK9 [55].”
Advances in Palmitoylation: A key Regulator of liver cancer development and therapeutic targets
Zhu, Z., Feng, S., Zeng, A., & Song, L. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116810 · Cited by 15
PCSK9 regulates the NODAL signaling pathway and cellular proliferation in hiPSCs
Roudaut, M., Idriss, S., Caillaud, A., Girardeau, A., Rimbert, A., Champon, B., David, A., Lévêque, A., Arnaud, L., Pichelin, M., et al. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.10.004 · Cited by 15
“, 2016), a recent article described PCSK9 as a regulator of the major histocompatibility protein class I (MHCI) recycling by promoting its relocation and degradation in the lysosome (Liu et al., 2020).”
BackgroundMechanical ventilation promotes lung tumour spread by modulation of cholesterol cell content
López-Alonso, I., López‐Martínez, C., Martín-Vicente, P., Amado‐Rodríguez, L., González-López, A., Colunga, J. M., Busto, C. D., Bernal, M., Crespo, I., Astudillo, A., et al. (2021) · European Respiratory Journal · doi:10.1183/13993003.01470-2021 · Cited by 16
Youssef, R., Maniar, R., Khan, J., & Mesa, H. A. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45120609 · Cited by 17
“Cholesterol-lowering agents such as PCSK9 inhibitors have demonstrated potentiation of checkpoint inhibitors in preclinical studies [88].”
BackgroundMeng, C., Zhang, H., Yi, X., Kong, G., Zhang, X., Wang, B., Xu, Y., Qi, H., Wu, Q., Zhang, K. K., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02480-x · Cited by 15
“In melanoma, PCSK9 can mediate MHC-I degradation through lysosome pathway [30].”
PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity
Alannan, M., Seidah, N. G., & Merched, A. J. (2022) · Cells · doi:10.3390/cells11244132 · Cited by 17
“The molecular mechanism by which CTL killed PCSK9-deficient tumor cells involved an increase in the tumor cell surface MHC I (Major Histocompatibility Complex I) expression in PCSK9-deficient tumors as compared to control, indicating that PCSK9 downregulates MHC I surface levels by lysosomal degradation in a manner ve…”
BackgroundTumor-intrinsic RGS1 potentiates checkpoint blockade response via ATF3-IFNGR1 axis
Wang, B., Jiang, B., Du, L., Chen, W., Zhang, Q., Chen, W., Ding, M., Cao, W., Gao, J., Deng, Y., et al. (2023) · OncoImmunology · doi:10.1080/2162402x.2023.2279800 · Cited by 14
“12 In addition, MHC class I (MHCI) mutations, 10 diminished transcription, 13 and degradation 14 also contribute to tumor immune evasion and checkpoint therapy resistance.”
BackgroundCancer and Cardiovascular Disease: The Conjoined Twins
Zmaili, M. A., Alzubi, J. M., Alkhayyat, M. M., Albakri, A. A., Alkhalaileh, F., Longinow, J., & Moudgil, R. (2024) · Cancers · doi:10.3390/cancers16081450 · Cited by 18
“These pathophysiological observations provoked the hypothesis of PCSK9 being a regulator of anti-tumor responses and thus, a potential target to enhance immunity against tumors [51].”
BackgroundInfluentialCholesterol metabolism in pancreatic cancer and associated therapeutic strategies
Daya, T., Breytenbach, A., Gu, L., & Kaur, M. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2024.159578 · Cited by 15
Metadata
- Authors
- Liu, X., Bao, X., Hu, M., Chang, H., Jiao, M., Cheng, J., Xie, L., Huang, Q., Li, F., & Li, C.-Y.
- Affiliations
- Sun Yat-sen University (CN)
- Duke Medical Center (US)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Duke University (US)
- Corresponding author
- Li, Chuan-Yuan
- Venue
- Nature
- Published
- 2020-11-11
- Volume
- 588
- Issue
- 7839
- Pages
- 693-698
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7770056
- OpenAlex
- W3103804121
- Cited by
- 490
- References
- 47
- Citations by year
- 2026: 60 · 2025: 107 · 2024: 106 · 2023: 81 · 2022: 73 · 2021: 60 · 2020: 2
- FWCI
- 17.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (2p30ca014236-51)
- National Cancer Institute (P30‐CA014236, R01 CA208852, R01CA216876)
- National Institute of Environmental Health Sciences (R01ES024015)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- PCSK9 inhibition, immune checkpoint therapy, anti-PD-1 therapy, cancer immunotherapy, cytotoxic T lymphocytes, tumor surveillance, lysosomal degradation, antigen presentation, tumor growth inhibition
- MeSH terms
- Proprotein Convertase 9, Immune Checkpoint Inhibitors, PCSK9 Inhibitors, Animals, Disease Models, Animal, Female, Humans, Immunotherapy, Lysosomes, Neoplasms, T-Lymphocytes, Cytotoxic, Histocompatibility Antigens Class I, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Antibodies, Neutralizing, Programmed Cell Death 1 Receptor
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