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.”
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Cited by
Sorted by citations
Turning cold tumors into hot tumors by improving T-cell infiltration
Liu, Y., & Sun, Z. (2021) · Theranostics · doi:10.7150/thno.58390 · Cited by 867
The hallmarks of cancer immune evasion
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Current advance of nanotechnology in diagnosis and treatment for malignant tumors
Wang, B., Hu, S., Teng, Y., Chen, J., Wang, H., Xu, Y., Wang, K., Xu, J., Cheng, Y., & Gao, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01889-y · Cited by 641
Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics
Jin, H.-R., Wang, J., Wang, Z., Xi, M., Xia, B., Deng, K., & Yang, J. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01498-2 · Cited by 537
“Moreover, inhibiting PCSK9, a key protein in the regulation of cholesterol metabolism, can boost the response of tumors to immune checkpoint therapy [317].”
BackgroundFu, T., Dai, L.-J., Wu, S.-Y., Xiao, Y., Ma, D., Jiang, Y.-Z., & Shao, Z.-M. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01103-4 · Cited by 480
“Spatial architecture of the TIME in clinical treatment To remodeling the spatial architecture of the TIME, diverse therapeutic strategies have also been proposed, including those that promote (116, 198) or prevent (199) immune cells from infiltrating into designated areas of the TIME, modify angiogenesis or oxygenatio…”
MethodResistance Mechanisms to Anti-PD Cancer Immunotherapy
Vesely, M. D., Zhang, T., & Chen, L. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-070621-030155 · Cited by 468
Macrophages at the interface of the co-evolving cancer ecosystem
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The role of lipid metabolic reprogramming in tumor microenvironment
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“A recent study published in Nature showed that PCSK9 knockout in mouse cancer cells substantially suppressed their growth in mice in a manner that depends on cytotoxic T cells [24].”
BackgroundThe Multifaceted Biology of PCSK9
Seidah, N. G., & Prat, A. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab035 · Cited by 232
Functional significance of cholesterol metabolism in cancer: from threat to treatment
Xiao, M., Xu, J., Wang, W., Zhang, B., Liu, J., Li, J., Xu, H., Zhao, Y., Yu, X., & Shi, S. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01079-w · Cited by 260
“In this case, the effects of PCSK9 inhibition in conjunction with an anti-PD-1 antibody treatment lead to a synergistic therapeutic outcome 91 .”
Targeting MHC-I molecules for cancer: function, mechanism, and therapeutic prospects
Wu, X., Li, T., Jiang, R., Yang, X., Guo, H., & Yang, R. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01899-4 · Cited by 223
“The study by Liu et al. similarly showed that PCSK9 Binds to pMHC-I to promote its degradation in lysosomes [114].”
BackgroundThe cholesterol pathway: impact on immunity and cancer
King, R. J., Singh, P. K., & Mehla, K. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.11.007 · Cited by 224
A membrane-associated MHC-I inhibitory axis for cancer immune evasion
Chen, X., Qiao, L., Zhou, H., Liu, J., Nadorp, B., Lasry, A., Sun, Z., Lai, B., Róna, G., Zhang, J., et al. (2023) · Cell · doi:10.1016/j.cell.2023.07.016 · Cited by 211
Luo, X., Wu, K., & He, X. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01968-w · Cited by 210
“Researchers also recently revealed that PCSK9, a critical negative regulator of lowdensity lipoprotein receptor (LDLR) that facilitates the degradation of LDLR, is associated with the regulation of T cell infiltration and CD8 T cell immunosuppression in tumors [121, 122].”
BackgroundFan, F., Liu, P., Bao, R., Chen, J., Zhou, M., Mo, Z., Ma, Y., Liu, H., Zhou, Y., Cai, X., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-1547 · Cited by 215
“Molecular cloning CRSIPR constructs were cloned following previously published method (17).”
MethodSelf-citationTargeting proprotein convertase subtilisin/kexin type 9 (PCSK9): From bench to bedside
Bao, X., Liang, Y., Chang, H., Cai, T., Feng, B., Gordon, K., Zhu, Y., Shi, H., He, Y., & Xie, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01690-3 · Cited by 187
“343 Moreover, several preclinical studies have substantiated that inhibition of PCSK9 through genetic depletion, 34,342,344 mAbs, 34,343,345,346 small molecule inhibitor, 342,346 nanoliposomal vaccine, 347 or siRNA 348 could effectively suppress tumor growth.”
BackgroundInfluentialSelf-citationYuan, J., Cai, T., Zheng, X., Ren, Y., Qi, J., Lü, X., Chen, H., Lin, H., Chen, Z., Liu, M., et al. (2021) · Protein & Cell · doi:10.1007/s13238-021-00821-2 · Cited by 168
“One research published recently also showed that PCSK9 can act as an efficient target in cancer immunotherapy (Liu et al., 2020).”
BackgroundPlebanek, M. P., Xue, Y., Nguyen, Y.-V., DeVito, N. C., Wang, X., Holtzhausen, A., Beasley, G. M., Theivanthiran, B., & Hanks, B. A. (2024) · Science Immunology · doi:10.1126/sciimmunol.adi4191 · Cited by 164
“The SREBP2 target gene Pcsk9 regulates MHC class I expression, and loss of Pcsk9 leads to enhanced MHC class I surface expression in several tumor types ( 40 ).”
BackgroundResultInfluentialTargeting PCSK9 to tackle cardiovascular disease
Hummelgaard, S., Vilstrup, J. P., Gustafsen, C., Glerup, S., & Weyer, K. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108480 · Cited by 150
Sun, Y., Zhang, H., Meng, J., Guo, F., Ren, D., Wu, H., & Jin, X. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111194 · Cited by 137
Verma, N. K., Wong, B. H. S., Poh, Z. S., Udayakumar, A., Verma, R., Goh, R. K. J., Duggan, S. P., Shelat, V. G., Chandy, K. G., & Grigoropoulos, N. F. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104216 · Cited by 130
Nanodiscs: a versatile nanocarrier platform for cancer diagnosis and treatment
Bariwal, J. B., Ma, H., Altenberg, G. A., & Liang, H. (2022) · Chemical Society Reviews · doi:10.1039/d1cs01074c · Cited by 130
“Cancer immunotherapy proved successful in achieving long-term survival in 10–30% of cancer patients; however, immune therapy utilizing immune checkpoint blockers is ineffective in most cases 161 because the therapeutic efficacy largely depends on pre-existing anti-tumor T-cells.”
BackgroundRegulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications
Xia, X.-D., Peng, Z.-S., Gu, H.-M., Wang, M., Wang, G.-Q., & Zhang, D.-W. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.764038 · Cited by 125
“This suppressed tumor growth of several mouse cancer cell lines, including 4T1 (breast cancer), MC38 (colon adenocarcinoma), and the PD-1 inhibitor-resistant cancer cell line, MC38R, in mice (7).”
BackgroundYang, L. G., Xu, F., Wang, Y., et al. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.121167 · Cited by 124
Lin, W., Chen, L., Zhang, H., Qiu, X., Huang, Q., Wan, F., Le, Z., Geng, S., Zhang, A., Qiu, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-35710-7 · Cited by 119
Self-citationHuang, J., Tsang, W. Y., Fang, X., Zhang, Y., Luo, J., Gong, L., Zhang, B., Wong, C. N., Li, Z.-H., Liu, B., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-0966 · Cited by 113
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Deng, G., Zhou, L., Wang, B., Sun, X., Zhang, Q., Chen, H., Wan, N., Ye, H., Wu, X., Sun, D., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-004874 · Cited by 114
Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy
Zou, W., & Green, D. R. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.06.003 · Cited by 122
Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models
Kansal, V., Burnham, A. J., Kinney, B. L. C., Saba, N. F., Paulos, C. M., Lesinski, G. B., Buchwald, Z. S., & Schmitt, N. C. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005940 · Cited by 109
Immune Checkpoint Therapies and Atherosclerosis: Mechanisms and Clinical Implications
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PCSK9 and cancer: Rethinking the link
Mahboobnia, K., Pirro, M., Marini, E., Grignani, F., Bezsonov, E. E., Jamialahmadi, T., & Sahebkar, A. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111758 · Cited by 112
Regulation of CD8+ T cells by lipid metabolism in cancer progression
Tang, Y., Chen, Z., Zuo, Q., & Kang, Y. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-024-01224-z · Cited by 124
“Clinically approved PCSK9-neutralizing antibodies synergize with anti-PD-1 therapy to inhibit tumor growth [94].”
BackgroundPCSK9 Inhibition: From Current Advances to Evolving Future
Liu, C., Chen, J., Chen, H., Zhang, T., He, D., Luo, Q., Chi, J., Hong, Z., Liao, Y., Zhang, S., et al. (2022) · Cells · doi:10.3390/cells11192972 · Cited by 108
“It has been reported that in different patient cohorts, individuals with high expression of tumor PCSK9 mRNA have a poorer overall survival rate than individuals with low expression of PCSK9 mRNA [21].”
BackgroundProprotein Convertase Subtilisin/Kexin Type 9
Macchi, C., Ferri, N., Sirtori, C. R., Corsini, A., Banach, M., & Ruscica, M. (2021) · American Journal Of Pathology · doi:10.1016/j.ajpath.2021.04.016 · Cited by 103
Novel strategies for cancer immunotherapy: counter-immunoediting therapy
Liu, S., Sun, Q., & Ren, X. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01430-8 · Cited by 107
“PCSK9 (a key protein that regulates cholesterol metabolism) was found to promote the re-localization and degradation of MHC-I in lysosomes to disrupt MHC-I recycling at the cell surface, while inhibition of PCSK9 induced a significant increase in MHC-I expression on tumor cells and enhanced the efficacy of anti-PD1 th…”
BackgroundWong, C. C., Wu, J.-L., Ji, F., Kang, W., Bian, X., Chen, H., Chan, L.-S., Luk, S. T. Y., Tong, S., Xu, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31663-z · Cited by 103
Atherosclerosis With Immune Checkpoint Inhibitor Therapy
Suero‐Abreu, G. A., Zanni, M. V., & Neilan, T. G. (2022) · JACC CardioOncology · doi:10.1016/j.jaccao.2022.11.011 · Cited by 104
“Specifically, its effect caused a significant increase in the expression of major histocompatibility protein class I, which enhanced intratumoral cytotoxic T cell infiltration.(99) In summary, recent studies have indicated a synergistic effect when ICI therapies are concomitantly used with statins and PCSK9 inhibitors…”
BackgroundAhn, G., Banik, S. M., & Bertozzi, C. R. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.02.024 · Cited by 98
“More recently, it was revealed that PCSK9 also traffics major histocompatibility protein class I (MHC I) from the tumor cell surface to the lysosome for degradation, and that inhibition of PCSK9 can induce intratumoral infiltration by T cells and improve the response to immune check point therapy (Liu et al., 2020).”
BackgroundPCSK9 promotes tumor growth by inhibiting tumor cell apoptosis in hepatocellular carcinoma
Zhang, S.-Z., Zhu, X., Feng, L.-H., Li, X., Liu, X., Sun, H., & Tang, Z. (2021) · Experimental Hematology and Oncology · doi:10.1186/s40164-021-00218-1 · Cited by 91
“In addition to regulating lipid transport, PCSK9 has many other effects on cell functions, such as in the processes of viral infection [29–31], insulin resistance [8, 32], development of the central nervous system [5], tumor apoptosis [9, 10] and tumor immunity [33, 34].”
BackgroundSelf-citationTurning cold tumors into hot tumors to ignite immunotherapy
Liu, Y., Wang, Y., Wang, S., Li, J., He, W. A., Fan, X.-J., & Wan, X. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02477-6 · Cited by 124
Lu, Z. F., McBrearty, N., Chen, J., Tomar, V. S., Zhang, H., Rosa, G. D., Tan, A., Weljie, A. M., Beiting, D. P., Miao, Z., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.08.007 · Cited by 89
Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity
Ma, M., Zhang, Y., Pu, K., & Tang, W. (2024) · Chemical Society Reviews · doi:10.1039/d4cs00679h · Cited by 100
Yang, Z., Liu, X., Zhu, J., Chai, Y., Cong, B., Li, B., Gao, W.-F., Hu, Y., Wen, M., Liu, Y., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.11.008 · Cited by 83
Self-citationExpanding biology of PCSK9: roles in atherosclerosis and beyond
Seidah, N. G., & Garçon, D. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01057-z · Cited by 76
Targeting MHC-I inhibitory pathways for cancer immunotherapy
Wang, J., Qiao, L., Chen, X., & Aifantis, I. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.01.009 · Cited by 82
PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation
Luquero, A., Badimón, L., & Borrell-Pagés, M. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.639727 · Cited by 77
“Therefore, PCSK9 decreases the cytotoxic T lymphocyte response against the tumor (90).”
BackgroundCholesterol Depletion‐Enhanced Ferroptosis and Immunotherapy via Engineered Nanozyme
Bai, T., Xue, P., Shao, S., Yan, S., & Zeng, X. (2024) · Advanced Science · doi:10.1002/advs.202405826 · Cited by 79
Seidah, N. G. (2021) · Journal of Lipid Research · doi:10.1016/j.jlr.2021.100130 · Cited by 78
“Independently from the LDLR, PCSK9 via the M2 module of its CHRD was also reported to bind MHC-I receptors and to target them to endosomes/lysosomes for degradation (135).”
BackgroundAnti-Inflammatory Effects of Lipid-Lowering Drugs and Supplements—A Narrative Review
Živković, S., Maric, G. D., Cvetinovic, N., Lepojevic-Stefanovic, D., & Božić, B. (2023) · Nutrients · doi:10.3390/nu15061517 · Cited by 75
“Moreover, data confirm that PCSK9 inhibition using alirocumab or evolocumab potentiates immune checkpoint inhibition therapy, specifically anti-PD1 antibody treatment, in mouse models of cancers [159].”
BackgroundHLA class I antigen processing machinery defects in antitumor immunity and immunotherapy
Maggs, L., Sadagopan, A., Moghaddam, A. S., & Ferrone, S. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.07.006 · Cited by 76
Li, J.-J., Wang, J.-H., Tian, T., Liu, J., Zheng, Y., Mo, H., Sheng, H., Chen, Y., Wu, Q., Han, Y., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42332-0 · Cited by 73
“First, we found that incubation with TAM-CM decreased FGL1 ubiquitination and prolonged its protein half-life in both MC38 and HT29 cells 30 (Fig.”
Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1
Ren, W., Xu, Z., Chang, Y., Ju, F., Wu, H., Liang, Z., Zhao, M., Wang, N., Lin, Y., Xu, C., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44466-7 · Cited by 68
“…through multiple tumor cell-intrinsic mechanisms, including upregulation of inhibitory immune checkpoint receptors 3 – 5 , impaired tumor antigen presentation 6,7 , secretion of inhibitory cytokines or ligands 8 – 10 and alterations in metabolic pathways 11,12 , as well as other mechanisms 13,14 .”
Proprotein convertase subtilisin/kexin type 9 (PCSK9): A potential multifaceted player in cancer
Bhattacharya, A., Chowdhury, A., Chaudhury, K., & Shukla, P. C. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188581 · Cited by 66
Zheng, M., Zhang, W., Chen, X., Guo, H., Wu, H., Xu, Y., He, Q., Ding, L., & Yang, B. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.10.027 · Cited by 68
Xie, W., Li, J., Du, H., & Xia, J. (2023) · Arthritis Research & Therapy · doi:10.1186/s13075-023-03122-7 · Cited by 65
“In addition to its effects on LDL-C levels, PCSK9i has potential pleiotropic effects, including enhancing the response of tumors to immune checkpoint therapy, suppressing platelet activation and thrombosis, and reducing cell apoptosis [34–36].”
BackgroundYu, X., Long, Y., Chen, B., Tong, Y., Shan, M., Jia, X., Hu, C., Liu, M., Zhou, J. Y., Tang, F., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-004590 · Cited by 73
“Accordingly, we have developed a type of PD-L1/TLR7 dual-targeting NDC with potent and broadly responsive antitumor activity and with potential for clinical development.”
Oxidative Stress and Reprogramming of Lipid Metabolism in Cancers
Li, S., Yuan, H., Li, L., Li, Q., Lin, P., & Li, K. (2025) · Antioxidants · doi:10.3390/antiox14020201 · Cited by 75
“Preclinical studies have demonstrated that PCSK9 can modulate immune responses by interacting with immune cells and TME components and have shown that there are synergies among alirocumab, evolocumab, and existing immunotherapies [166].”
Ning, W.-R., Jiang, D., Liu, X.-C., Huang, Y.-F., Peng, Z.-P., Jiang, Z.-Z., Kang, T., Zhuang, S.-M., Wu, Y., & Zheng, L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci153110 · Cited by 66
“previously described (52), and the expression of different markers in”
BackgroundSelf-citationPoels, K., Neppelenbroek, S. I. M., Kersten, M. J., Antoni, M. L., Lutgens, E., & Seijkens, T. T. P. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002916 · Cited by 64
Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion
Yan, R., Zhang, P., Shen, S., Zeng, Y., Wang, T., Chen, Z., Ma, W., Feng, J., Suo, C., Zhang, T., et al. (2024) · Nature Immunology · doi:10.1038/s41590-023-01719-3 · Cited by 64
Anatomy and physiology of word-selective visual cortex: from visual features to lexical processing
Caffarra, S., Karipidis, I. I., Yablonski, M., & Yeatman, J. D. (2021) · Brain Structure and Function · doi:10.1007/s00429-021-02384-8 · Cited by 69
Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities
Jiang, W. G., Jin, W., & Xu, A. (2024) · International Journal of Biological Sciences · doi:10.7150/ijbs.92274 · Cited by 70
Receptor-interacting Protein Kinase 2 Is an Immunotherapy Target in Pancreatic Cancer
Sang, W., Zhou, Y., Chen, H., Yu, C., Dai, L., Liu, Z., Chen, L., Fang, Y., Ma, P., Wu, X., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0584 · Cited by 61
Guo, W., Gao, H., Li, H., Ge, S., Zhang, F., Wang, L., Shi, H., & Han, A. (2022) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.2c06001 · Cited by 60
Wang, R., Liu, H., He, P., An, D., Guo, X., Zhang, X., & Feng, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.947756 · Cited by 58
“Inhibiting PCSK9 by small molecular compounds or monoclonal antibodies increases the expression of MHC I on the tumor cell surface, promoting intratumoral infiltration of cytotoxic lymphocytes (17, 18).”
BackgroundFunctions and mechanisms of lactylation in carcinogenesis and immunosuppression
Su, J., Zheng, Z., Bian, C., Chang, S., Bao, J., Yu, H., Xin, Y., & Jiang, X. M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1253064 · Cited by 57
Fang, S., Yarmolinsky, J., Gill, D., Bull, C. J., Perks, C. M., the PRACTICAL Consortium, Davey Smith, G., Gaunt, T. R., & Richardson, T. G. (2023) · PLOS Medicine · doi:10.1371/journal.pmed.1003988 · Cited by 55
“Additionally, Liu and colleagues inoculated Pcsk9 knockout mouse cancer cells into syngeneic mouse hosts and observed delayed tumour growth, as well as a synergistic effect between PCSK9 inhibition and anti-PD1 antibody treatment to promote the efficacy of tumour growth suppression [64].”
BackgroundSynergistic Brilliance: Engineered Bacteria and Nanomedicine Unite in Cancer Therapy
Zhou, Y., Li, Q., Wu, Y., Zhang, W., Ding, L., Ji, C., Li, P., Chen, T., Feng, L., Tang, B. Z., et al. (2024) · Advanced Materials · doi:10.1002/adma.202313953 · Cited by 59
Immune checkpoint inhibitors associated cardiovascular immune-related adverse events
Jo, W., Won, T., Daoud, A., & Čiháková, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1340373 · Cited by 55
“Studies have shown that combining PCSK9 with ICIs improves intra-tumoral cytotoxic T cell in fi ltration, antigen presentation, and the expression of co-inhibitory checkpoint molecules (205 – 207).”
BackgroundResultAn Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy
Zhang, D., Li, Q., Chen, X., Nie, X., Xue, F., Xu, W., & Luan, Y. (2022) · Small · doi:10.1002/smll.202202663 · Cited by 57
Our evolving understanding of how 27-hydroxycholesterol influences cancer
Ma, L., Cho, W., & Nelson, E. R. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114621 · Cited by 53
Siltari, A., Syvälä, H., Lou, Y., Gao, Y., & Murtola, T. J. (2022) · Cancers · doi:10.3390/cancers14174293 · Cited by 53
“Knockdown of protein convertase subtilisin/kexin 9 (PCSK9) resulted in less extensive xenograft growth and longer survival times in breast cancer, colon cancer, and melanoma xenografts [92].”
BackgroundSadagopan, A., Michelakos, T. P., Boyiadzis, G., Ferrone, C. R., & Ferrone, S. (2021) · JAMA Oncology · doi:10.1001/jamaoncol.2021.5970 · Cited by 49
PCSK9 in metabolism and diseases
Ajoolabady, A., Pratico, D., Mazidi, M., Davies, I. G., Lip, G. Y. H., Seidah, N., Libby, P., Kroemer, G., & Ren, J. (2025) · Metabolism · doi:10.1016/j.metabol.2024.156064 · Cited by 49
Zhang, H., Zhao, W., Li, X., & He, Y. (2021) · OncoTargets and Therapy · doi:10.2147/ott.s315998 · Cited by 49
“Recent studies have shown that PCSK9 inhibitors synergistically inhibit tumor growth in mouse tumor model with anti-PD1 antibodies.(68) It has been reported that the inhibition of PCSK9 can significantly increase the expression of MHC II on the surface of tumor cells, thereby promoting infiltration of cytotoxic T-cell…”
BackgroundInfluentialStatins in Cancer Prevention and Therapy
Ricco, N., & Kron, S. J. (2023) · Cancers · doi:10.3390/cancers15153948 · Cited by 53
“Significantly, PCSK9 has a similar effect on MHC I, leading to its lysosomal transport and downregulation [78].”
BackgroundKong, S., Zhang, J., Wang, L., Li, W., Guo, H., Weng, Q., He, Q., Lou, H., Ding, L., & Yang, B. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217432 · Cited by 50
Cancer therapy's impact on lipid metabolism: Mechanisms and future avenues
Bhatnagar, R., Dixit, N. M., Yang, E. H., & Sallam, T. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.925816 · Cited by 48
“For example, one study found that PCSK9 inhibition in mice potentiated the anti-tumor effects of ICI therapy, although the direct effects of lipid metabolism have yet to be studied (158).”
BackgroundImmune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection
Zhang, X., Xu, H., Yu, J., Cui, J., Chen, Z., Li, Y., Niu, Y., Wang, S., Ran, S., Zou, Y., et al. (2023) · Circulation · doi:10.1161/circulationaha.123.062788 · Cited by 50
PCSK9: A emerging participant in heart failure
Xu, Q., Zhao, Y.-M., He, N.-Q., Gao, R., Xu, W., Zhuo, X.-J., Ren, Z., Wu, C., & Liu, L. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114106 · Cited by 47
Molecular Mechanisms of Resistance to Immune Checkpoint Inhibitors in Melanoma Treatment: An Update
Vukadin, S., Khaznadar, F., Kizivat, T., Včev, A., & Smolić, M. (2021) · Biomedicines · doi:10.3390/biomedicines9070835 · Cited by 47
“One study showed that PCSK9 neutralization improved the efficacy of ICI in melanoma in a mouse model [138].”
BackgroundQuagliariello, V., Bisceglia, I., Berretta, M., Iovine, M., Canale, M. L., Maurea, C., Giordano, V., Paccone, A., Inno, A., & Maurea, N. (2023) · Cancers · doi:10.3390/cancers15051397 · Cited by 44
The role of PCSK9 in inflammation, immunity, and autoimmune diseases
Frostegård, J. (2022) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2022.2017281 · Cited by 43
“check point immune therapy against cancer tumors [59].”
BackgroundTumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation
Zhang, B., Li, J., Hua, Q., Wang, H., Xu, G., Chen, J., Zhu, Y., Li, R., Liang, Q. D., Wang, L., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005592 · Cited by 46
Association between abnormal lipid metabolism and tumor
Li, C., Wang, F., Cui, L., Li, S., Zhao, J., & Liao, L. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1134154 · Cited by 42
Self-citationKatsi, V. K., Papakonstantinou, I. P., & Tsioufis, K. P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411786 · Cited by 43
Zhou, X., Wang, G., Tian, C., Du, L., Prochownik, E. V., & Li, Y. (2024) · Nature Communications · doi:10.1038/s41467-024-50138-x · Cited by 47
“For instance, PCSK9 regulates the expression of MHC-I on the tumor cells and its inhibitionpromotesrobustcytotoxicTcellin fi ltration 33,34 .”
Immune checkpoint landscape of human atherosclerosis and influence of cardiometabolic factors
Durán, J. G. B., Das, D., Gildea, M. A., Amadori, L., Gourvest, M., Kaur, R., Eberhardt, N., Smyrnis, P., Cılhoroz, B., Sajja, S., et al. (2024) · Nature Cardiovascular Research · doi:10.1038/s44161-024-00563-4 · Cited by 48
“PCSK9 inhibition dramatically lowers low-density lipoprotein (LDL) cholesterol 62,63 and increases the efficacy of IC therapies in cancer 64–66 , without increasing the risk of developing T2D, unlike statins 67,68 .”
Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications
Lu, J., Chen, S., Bai, X., Liao, M., Qiu, Y., Zheng, L., & Yu, H. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115907 · Cited by 44
Targeting PCSK9: a promising adjuvant strategy in cancer immunotherapy
Almeida, C. R., Ferreira, B. H., & Duarte, I. F. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00530-6 · Cited by 41
“found that PCSK9 interacts with MHC I and promotes its trafficking to the lysosomes and subsequent degradation, while blocking its recycling back to the membrane.(1) As a consequence, cells expressing PCSK9 have reduced levels of surface MHC I and thus escape CTL recognition, while PCSK9 deficiency or inhibition promo…”
BackgroundInfluentialTargeting lipid metabolism in metastatic prostate cancer
Scheinberg, T., Mak, B., Butler, L. M., Selth, L. A., & Horvath, L. G. (2023) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359231152839 · Cited by 50
The evolving landscape of PCSK9 inhibition in cancer
Oza, P. P., & Kashfi, K. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.175721 · Cited by 43
Seidah, N. G., Pasquato, A., & Andréo, U. (2021) · Viruses · doi:10.3390/v13071229 · Cited by 41
“, LDLR and MHC-class I receptor) toward 90 lysosomes for degradation [16-19].”
BackgroundRecent Advances in Functional Carbon Quantum Dots for Antitumour
Cai, R., Xiao, L., Liu, M., Du, F., & Wang, Z. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s334012 · Cited by 43
Clearance of plasma PCSK9 via the asialoglycoprotein receptor mediated by heterobifunctional ligands
Bagdanoff, J. T., Smith, T. M., Allan, M., O’Donnell, P. H., Nguyen, Z., Moore, E. A., Baird, J., Wang, S., Subramanian, V., Tigani, B., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2022.12.003 · Cited by 42
De Lellis, L., Veschi, S., Tinari, N., Mokini, Z., Carradori, S., Brocco, D., Florio, R., Grassadonia, A., & Cama, A. (2021) · Cancers · doi:10.3390/cancers13163946 · Cited by 40
“PCSK9-neutralizing antibodies increase the expression of MHC-I proteins by promoting their recycling to the surface of tumor cells and, therefore, opposing their lysosomal degradation [223].”
BackgroundLipid Nanoparticles for mRNA Delivery to Enhance Cancer Immunotherapy
Wang, H., Wang, Z.-G., & Liu, S. (2022) · Molecules · doi:10.3390/molecules27175607 · Cited by 41
“In addition, inhibition of PCSK9 by gene deletion or other methods promotes the action of major histocompatibility protein class I (MHC I) proteins on cancer cells and enhances tumor infiltration of T cells [94,95].”
MethodA commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor
Mei, W., Tabrizi, S. F., Godina, C., Lovisa, A. F., Isaksson, K., Jernström, H., & Tavazoie, S. F. (2024) · Cell · doi:10.1016/j.cell.2024.11.009 · Cited by 43
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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