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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- 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.
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.”
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Cited by
Sorted by citations
Items 401–490 of 490
Oduah, E. I., Zhang, T., Jung, S.-H., Stinchcombe, T. E., Ready, N., Crawford, J., Clarke, J. M., Gray, J. E., & Antonia, S. J. (2026) · Future Oncology · doi:10.1080/14796694.2026.2648863
Potentiating CD8 + T cell antitumor activity by targeting the PCSK9/LDLR axisPreprint
Yuan, J., Cai, T., Zheng, X., Ren, Y., Qi, J., Lü, X., Chen, H., Lin, H., Chen, Z., Liu, M., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.12.03.403121
“…and a therapeutic drug target for treating hypercholesterolemia, has been implicated in a critical role for regulating LDLR protein levels via mediating LDLR internalization and degradation (Abifadel et al., 2003; Maxwell et al., 2005; Cunningham et al., 2007; Zhang et al., 2007; Liu et al., 2020).”
BackgroundIntroduction to prostate cancer metabolism and treatment with nonconventional drugs
Koltai, T., Reshkin, S. J., Baltazar, F., & Fliegel, L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-90528-2.00010-2
Research Progress of PD-1 Inhibitor Combination
陈, 岳. (2021) · Pharmacy Information · doi:10.12677/pi.2021.103015
Circulating 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) · Journal of clinical lipidology · doi:10.1016/j.jacl.2021.09.007 · Cited by 3
Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancersPreprint
Chong, E. W., Joncas, F., Seidah, N. G., Calon, F., Diorio, C., & Gangloff, A. (2022) · Research Square · doi:10.21203/rs.3.rs-1412728/v1
Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancersPreprint
Chong, E. W., Joncas, F., Seidah, N. G., Calon, F., Diorio, C., & Gangloff, A. (2022) · Research Square · doi:10.21203/rs.3.rs-1420016/v2
Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancersPreprint
Chong, E. W., Joncas, F., Seidah, N. G., Calon, F., Diorio, C., & Gangloff, A. (2022) · Research Square · doi:10.21203/rs.3.rs-1420016/v3
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Self-citationPreclinical Cancer Models for the Evaluation of Immunotherapies: From Cell Lines to Animal Models
Pezeshki, P. S., & Rezaei, N. (2022) · Springer eBooks · doi:10.1007/978-3-030-80962-1_206-1
Peng, L., Zhou, L., Li, H., Lu, D., Qian, M., & Wang, Z. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.25.530003
“At present, only 10-30% of treated patients benefits from cancer immunotherapy (16).”
BackgroundResearch Progress of PCSK9 Function in Tu-mor Microenvironment of Breast Cancer
慕, 玉. (2023) · Medical Diagnosis · doi:10.12677/md.2023.131008
Fan, F., Liu, P., Bao, R., Chen, J., Zhou, M., Mo, Z., Ma, Y., Liu, H., Zhou, Y., Cai, X., et al. (2023) · doi:10.1158/0008-5472.c.6513597.v1
Self-citationEmerging Lipoprotein-Related Therapeutics for Patients with Diabetes
Bobik, A., Cohen, N. D., Jenkins, A. J., Kyaw, T. S., SULLIVAN, D. R., Wu, X., Yu, X.-Y., & Little, P. J. (2023) · Contemporary diabetes · doi:10.1007/978-3-031-26681-2_30
Peña, G. A. S., Armas, G. F. A., Terán, G. A. D., Serrano, S. P. P., Reyes, A. C. C., Taboada, D., & Chango, G. K. C. (2023) · Salud Ciencia y Tecnología · doi:10.56294/saludcyt2023587
Zahid, A., Batool, A., Khan, M. A., Ahmad, A., Ullah, A., & Wajid, A. (2024) · Research Square · doi:10.21203/rs.3.rs-4684994/v1
Serum Level and Clinical Significance of PCSK9 and MIF in Breast Cancer
慕, 玉. (2024) · Medical Diagnosis · doi:10.12677/md.2024.143050
Zahid, A., Batool, A., Khan, M. A., Ahmad, A., Ullah, A., & Wajid, A. (2024) · Research Square · doi:10.21203/rs.3.rs-4684994/v2
Applications of CRISPR technology
Du, Z. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23865-9.00003-4
Wang, Q., Yang, Z., Zhao, P., Lin, X., Wen, S., Zhang, X., & Xu, Y. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5080363
Lipid‐Lowering Drugs and Pulmonary Vascular Disease: A Mendelian Randomization Study
Yuan, X., Hong, P., & Zhou, J. (2025) · Pulmonary Circulation · doi:10.1002/pul2.70043
Solomon, N., Scharff, Y., Rubinstein, Y., Monteran, L., Ershaid, N., Cohen, N., Zait, Y., Aizic, A., Laskov, I., Grisaru, D., et al. (2025) · International Journal of Gynecological Cancer · doi:10.1016/j.ijgc.2024.101129
Flavonoids from the leaves of Monanthotaxis filipes modulate PCSK9 and LDLR
Mayeka, J. G., Atilaw, Y., Shadrack, D. M., Sarnyai, F., Csala, M., Németh, K., Nyandoro, S. S., Tamási, V., Erdélyi, M., & Munissi, J. J. E. (2025) · Scientific African · doi:10.1016/j.sciaf.2025.e02709 · Cited by 1
Xu, J., Lv, Y., Zhu, Z., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-5509842/v1
PCSK9 inhibitors: A comprehensive analysis of the clinical trial landscape
Lu, Y., & Jiang, H. T. (2025) · Asian Journal of Surgery · doi:10.1016/j.asjsur.2025.03.111
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“46] The role of PCSK9i and HMGCRi in inflammation and endocrine function, particularly in relation to the pathogenesis of REDs, has garnered considerable attention in recent times.”
Zhang, X., Yang, Z., & Huang, R. (2025) · Clinical Medicine and Pharmacology · doi:10.70731/91pd8g49
Do Anti-PCSK9 Monoclonal Antibodies Have Pleiotropic Effects?
Ferri, N. (2025) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2025.04.005
A Causal Relationship Between Genetically Proxied Inhibition of HMGCR, NPC1L1, and PCSK9 and Cancers
Wang, X., Zeng, Y., Xu, Z., et al. (2025) · MedComm – Oncology · doi:10.1002/mog2.70026
Cancer cells impede T cell early activation and drive immune evasion by transferring Tmem176bPreprint
Xiao, N., Gao, X., Liu, F., You, A., Jin, Y., Luo, F., Zhang, Q., Lan, Z., Xie, J., Zeng, Q., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-6199894/v1
A marker for sterol-dependent metastatic tropism
Wang, Y., Wang, X., David, C. J., & Zou, Y. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01626-1
Treatment of dyslipidemia: PCSK-9 in focus
Lukač, S. S., Popović, L., Rasulić, I., Petakov, A., Bogdanović, J. M., Mitrović, M., Krstic, M., & Lalic, K. S. (2025) · Medicinska istrazivanja · doi:10.5937/medi0-55356
Preclinical Cancer Models for the Evaluation of Immunotherapies: From Cell Lines to Animal Models
Pezeshki, P. S., & Rezaei, N. (2025) · Springer eBooks · doi:10.1007/978-3-032-00767-4_206
Shi, C., Wu, T., Niu, Z., Wang, Y., Zhao, H., Gui, Y., Wang, C., Xiao, K., Yuan, W., Wang, B., et al. (2025) · Materials & Design · doi:10.1016/j.matdes.2025.115121
Yeh, J., Chen, H., Lan, X., Huang, C., Chen, Y.-L., Wang, Y.-T., Shao, P., Ko, S., Guo, J., & Yip, H. (2025) · International Journal of Surgery · doi:10.1097/js9.0000000000003728
Leiva, O., DeCara, J. M., Yang, E. H., Gozdecki, L., Kanelidis, A., & Swat, S. A. (2025) · Future Cardiology · doi:10.1080/14796678.2025.2594947
Chen, F., Xie, W., Yu, J., Ye, J., Zhang, L., Lin, B., Gu, L., & Liu, W. (2025) · Journal of Asthma · doi:10.1080/02770903.2025.2589789
“Moreover, cholesterol and its regulatory gene proprotein convertase subtilisin/kexin type 9 (PCSK9) have been implicated in immune checkpoint modulation, further highlighting the immunoregulatory role of lipids (27).”
Maranou, E., Park, G., Weinzettl, P., Alanko, J., Pulkkinen, O. I., Coupland, S. E., Salmi, M., & Figueiredo, C. R. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.01.691518
Wang, H., Zhang, X., Zhang, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25583929
Zhong, P., Nakata, K., Oyama, K., Higashijima, N., Sagara, A., Date, S., Luo, H., Hayashi, M., Kubo, A., Wu, C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26717547
Zhong, P., Nakata, K., Oyama, K., Higashijima, N., Sagara, A., Date, S., Luo, H., Hayashi, M., Kubo, A., Wu, C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26717550
Zhong, P., Nakata, K., Oyama, K., Higashijima, N., Sagara, A., Date, S., Luo, H., Hayashi, M., Kubo, A., Wu, C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26717556
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Zhong, P., Nakata, K., Oyama, K., Higashijima, N., Sagara, A., Date, S., Luo, H., Hayashi, M., Kubo, A., Wu, C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26717553
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Luo, X.-Y., Wu, K.-M., & He, X.-X. (2021) · Figshare · doi:10.6084/m9.figshare.14615275
Zhong, P., Nakata, K., Oyama, K., Higashijima, N., Sagara, A., Date, S., Luo, H., Hayashi, M., Kubo, A., Wu, C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26717541
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Xie, W., Li, J., Du, H., & Xia, J. (2023) · Figshare · doi:10.6084/m9.figshare.23949684
Li, J., Yang, Z., Wang, T., Li, M., Wu, X., Fu, X., Yang, C., Li, Y., Wang, X., Lan, Z., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25951854
Li, C., Tan, H., Mao, Y., Liu, Y., Hu, J., Pang, X., Hou, X., & Minglin, O. (2025) · Network Modeling Analysis in Health Informatics and Bioinformatics · doi:10.1007/s13721-025-00695-y
“( L ) Heatmap of GMII distribution, patient survival, and expression profiles of the eight genes that comprise GMII in the GES37745 cohort 1 3 effect of tumor immunotherapy and may be a new target for tumor immunotherapy (Liu et al. 2020).”
Self-citationAssociation of PCSK9 inhibitors versus statins with cancer incidence: a target trial emulation
Huang, C.-H., Wang, S., Fan, F. S., Lu, H.-J., & Wei, J. C. (2026) · Cardio-Oncology · doi:10.1186/s40959-025-00436-0
“Furthermore, research by Liu et al. demonstrated that PCSK9i can synergize with anti-PD1 ICI therapy to suppress tumor growth in murine models [33].”
Agmon, I. N., Gurevitz, C., Shochat, T., Kushnir, S., Witberg, G., Levi, A., Gilon, D., Kornowski, R., Thavendiranathan, P., Abdel-Qadir, H. M., et al. (2026) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.70232
Research Progress of PCSK9 and Its Inhibitors in the Treatment of Hepatocellular Carcinoma
刘, 亚. (2026) · Pharmacy Information · doi:10.12677/pi.2026.152014
Huang, K., & Ren, J. P. (2026) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2025.33
Etude du rôle de la protéine PCSK9 dans la cellule bêta pancréatique
Saitoski, K. (2021) · theses.fr (ABES) · doi:10.70675/58b8c006z57e2z47a2zbb66z1e469544d6a5
Luo, J., Tang, B., Zhang, X., Hu, Y., Fang, S., Yang, Y., Shu, G., Song, J., Zhao, Z., Karimi, H. R., et al. (2026) · Engineering · doi:10.1016/j.eng.2026.04.007
The role of YY1 in promoting cancer immune evasion
Li, M., Zhang, J., Fan, R., Liu, M., Li, D., & Sui, G. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189595
The role of PCSK9 in cancer risk: Population-level evidence and mechanistic insights
Liu, H., Zhou, T., Wang, L., Liu, F., & Gu, D. (2026) · Oncology and Translational Medicine · doi:10.1097/ot9.0000000000000141
The secretory PCSK family in cardiovascular disease and beyond
Seidah, N. G. (2026) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2026.120716
Li, Z., Sun, C., Zhang, Q., Ji, L., Zhang, Y., Li, S., Gu, M., Gao, J., Huang, Z., Wang, M., et al. (2026) · Journal of Inflammation Research · doi:10.2147/jir.s590179
Gao, R., Xu, X., Zhou, Y., Lan, C., Xu, Z., Li, D., Chen, H., Li, K., & Wang, H. (2026) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2026.140688
Overcoming resistance to anti-PD-1/PD-L1 therapy in cancer
Li, L., Zhao, Y., Shi, X., Guo, X., Zhang, X., Li, G., Meng, Q., Zhang, M., & Yin, M. (2026) · Cancer Drug Resistance · doi:10.20517/cdr.2026.12
A narrative review of PCSK9 inhibitors: from evolocumab to novel discoveries
Liu, H., Li, S. N., & Li, J. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1800502
Lafortune, C., Haddad, Y., Marcinkiewicz, M. M., Chrétien, M., Turcotte, S., & Mbikay, M. (2026) · Lipids in Health and Disease · doi:10.1186/s12944-026-02981-8
Use of PCSK9 Inhibitors Among Patients Receiving Immune Checkpoint Inhibitors for Cancer
Lu, C., Jiang, C., Wang, A. Z., & Zhang, T. (2026) · JAMA Network Open · doi:10.1001/jamanetworkopen.2026.12707
Martín, A., García-Escudero, M. D., García, H. M., Bañares, I., Fontal, N., Eguia, J., Gallastegui, P. G., Benito, A. V., SÁEZ, F. J., Crende, O., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.26.727886
Kounatidis, D. C., Vallianou, N. G., Panagopoulos, F., Bampiolakis, A., Stamatopoulos, V., Dalamaga, Μ., Mourouzis, I. S., & Pantos, C. I. (2026) · Biomolecules · doi:10.3390/biom16060831
“Conversely, PCSK9 inhibition increased tumor-cell surface MHC-I levels, enhanced antigen presentation, and improved CD8 + T-cell-mediated antitumor activity [178].”
Martin, A., García, H. M., Bañares, I., Khatib, A., & Badiola, I. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105429
Zhang, Z., Gu, Y., Qiao, S., Sang, L., Zhang, L., & Zhou, F. (2026) · Cell Press Blue · doi:10.1016/j.cpblue.2026.100056
Amino Acid and Lipid Metabolism in Cancer: Mechanisms and Therapeutic Opportunities
Wang, Z., Fu, X., Bai, J., Liu, Y., & Huang, K. (2026) · MedComm · doi:10.1002/mco2.70886
“…metabolic; for example, PCSK9 inhibition improves responses to immune checkpoint therapy through a mechanism reported to be independent of classic cholesterol-lowering logic, emphasizing that lipid regulators can control antigen presentation and immune susceptibility via unexpected routes [ 108 ].”
InfluentialThe Impact of PCSK9 Inhibitors on Circulatory Inflammation
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“Liu et al. reported that PCSK9, by associating with MHC-I and promoting its lysosomal degradation, diminishes antigen presentation and facilitates immune evasion, while its inhibition promotes CD8 + T cell expansion (Liu et al., 2020).”
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Cholesterol in hematological malignancies: metabolism, mechanisms, and clinical implications
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Berberine and Etoposide Exert Synergistic Anticancer Effects in A431 Epidermoid Carcinoma Cells
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Self-citation
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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