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.”
Citations
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Genome-scale CRISPR-Cas9 knockout screening in human cells
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Nivolumab plus Ipilimumab in Advanced Melanoma
Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Segal, N. H., Ariyan, C. E., Gordon, R.-A., Reed, K., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1302369 · Cited by 4,230
Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer
Zhang, L., Conejo-Garcia, J. R., Katsaros, D., Gimotty, P. A., Massobrio, M., Regnani, G., Makrigiannakis, A., Gray, H., Schlienger, K., Liebman, M. N., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa020177 · Cited by 3,397
T cell receptor antagonist peptides induce positive selection.
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Cited by
Sorted by citations
Items 201–300 of 490
Regulating tumor cells to awaken T cell antitumor function and enhance melanoma immunotherapy
Zhang, W., Yuan, S., Zhang, Z., Fu, S., Liu, S., Liu, J., Ma, Q., Xia, Z., Gu, P., Gao, S., et al. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.123034 · Cited by 16
Saitoski, K., Ryaboshapkina, M., Hamza, G. M., Jarnuczak, A. F., Berthault, C., Carlotti, F., Armanet, M., Sengupta, K., Underwood, C. R., Andersson, S., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102096 · Cited by 15
“Very recently, it was also demonstrated that PCSK9 disrupts the recycling of major histocompatibility complex I (MHC-I) to the cell surface, thus positioning PCSK9 inhibitors as a new way to enhance immune checkpoint therapy for cancer (24).”
BackgroundThe Role of PCSK9 in Infectious Diseases
Magnasco, L., Sepulcri, C., Antonello, R. M., Bella, S. D., Labate, L., Luzzati, R., Giacobbe, D. R., & Bassetti, M. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867328666210714160343 · Cited by 13
ATRA promotes PD-L1 expression to control gastric cancer immune surveillance
Ma, Z., Ding, Y.-L., Jing, J., Du, L., Zhang, X.-Y., Liu, H., & He, P. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.174822 · Cited by 14
Comprehensive prognostic and immunological analysis of CCT2 in pan-cancer
Lv, W., Shi, L., Pan, J., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.986990 · Cited by 13
Wüster, J., Heiland, M., Nahles, S., Preißner, R., & Preißner, S. (2023) · Cancers · doi:10.3390/cancers15123093 · Cited by 13
“Other cholesterol-lowering drugs, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, seem to potentiate immune checkpoint therapy in cancer patients [45] and might even be used as a potential future therapeutic target in personalized cancer medicine [46].”
BackgroundDysregulation of Cholesterol Homeostasis in Ovarian Cancer
Qusairy, Z., Gangloff, A., & Leung, S. O. A. (2023) · Current Oncology · doi:10.3390/curroncol30090609 · Cited by 13
“This disturbance in cholesterol homeostasis is achieved by blocking sensor genes to high cholesterol levels and upregulating the genes and enzymes that are involved in the production and uptake of cholesterol [11,28,40].”
BackgroundZheng, R., Huang, C., Zhou, H., Zhao, L., Li, Q., Chen, G., Zhao, L., & Li, S. (2024) · Aggregate · doi:10.1002/agt2.610 · Cited by 13
Dong, H., Wen, C., He, L., Zhang, J., Xiang, N., Liang, L., Hu, L., Li, W., Liu, J., Shi, M., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05572-2 · Cited by 15
“P > 0.05, * P 0.05, ** P 0.01, *** P 0.001, **** P 0.0001 metabolism, can promote lysosomal MHC I degradation and influence the tumor immune response [34, 35].”
BackgroundInfluentialEngineered extracellular vesicles as nanosponges for lysosomal degradation of PCSK9
Wang, C., Zhou, X., Bu, T., Liang, S., Hao, Z., Qu, M., Liu, Y., Wei, M., Xing, C., Yang, G., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.11.034 · Cited by 13
Insights Into Heart-Tumor Interactions in Heart Failure
Caller, T., Moore, K. J., Lehmann, L., Wu, S. M., & Leor, J. (2025) · Circulation Research · doi:10.1161/circresaha.124.325490 · Cited by 15
A new enhancer for anti-PD-1/PD-L1 immunotherapy: PCSK9 inhibition
Sun, S., Yang, Z., Yao, H., & Zhang, Z. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.10.002 · Cited by 12
Advances in targeting protein S-palmitoylation in tumor immunity and therapy
Han, M., Lv, Y., Chen, Y., Li, Z., Tian, J., Zhou, H., Wang, Y., Su, W., & Zhong, J. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1547636 · Cited by 12
“The down-regulation of preprotein convertase Bacillus subtilis protease/kexin type 9 (PCSK9) augments tumor in fi ltration by cytotoxic T-cells, improves the effectiveness of anti-PD-1 therapies, and is pivotal in the anti-tumor immune response (130).”
Research progress on cholesterol metabolism and tumor therapy
Chu, Z., Fang, L., Xiang, Y., & Ding, Y. (2025) · Discover Oncology · doi:10.1007/s12672-025-02430-5 · Cited by 14
“Studies have shown that knocking out PCSK9 significantly enhances this capacity [78].”
Tombling, B. J., Lammi, C., Bollati, C., Anoldi, A., Craik, D. J., & Wang, C. K. L. (2021) · ChemBioChem · doi:10.1002/cbic.202100103 · Cited by 12
PCSK9 as a New Player in Cancer: New Opportunity or Red Herring?
Bonaventura, A., Vecchié, A., Ruscica, M., Grossi, F., & Dentali, F. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867328666211115122324 · Cited by 13
Research on Hepatocyte Regulation of PCSK9-LDLR and Its Related Drug Targets
Liu, S.-S., Yu, T., Qiao, Y.-F., Gu, S.-X., & Chai, X.-L. (2024) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-023-3545-z · Cited by 11
“(73 ) Further exploration of function of PCSK9/LDLR may be important for the treatment of multiple related lipid metabolic diseases in humans.”
Li, T., Wu, R., & Luo, K. Q. (2025) · Advanced Science · doi:10.1002/advs.202408514 · Cited by 12
Ungvari, Z. I., Menyhárt, O., Lehoczki, A., Fekete, M., Bianchini, G., & Győrffy, B. (2025) · GeroScience · doi:10.1007/s11357-025-01733-3 · Cited by 11
“Inhibition of PCSK9 can enhance major histocompatibility complex class I (MHC-I) expression on tumor cells, increasing their recognition by cytotoxic T cells and improving immune-mediated tumor clearance [2, 5, 17].”
InfluentialXu, W., Lu, X., Liu, J., Chen, Q., Huang, X., Huang, K., Liu, H., Zhu, W., & Zhang, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.700700 · Cited by 11
Serum cholesterol and the risk of developing hormonally driven cancers: A narrative review
Murdock, D. J., Sanchez, R. J., Mohammadi, K. A., Fazio, S., & Geba, G. P. (2022) · Cancer Medicine · doi:10.1002/cam4.5463 · Cited by 11
Cendron, L., Rothenberger, S., Cassari, L., Dettin, M., & Pasquato, A. (2022) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2022.10.001 · Cited by 12
Su, X., Dosset, M., Castro, A., Carter, H. K., & Zanetti, M. (2023) · PNAS Nexus · doi:10.1093/pnasnexus/pgad046 · Cited by 14
Abdelwahed, K. S., Siddique, A. B., Ebrahim, H. Y., Qusa, M. H., Mudhish, E. A., Rad, A. H., Zerfaoui, M., Elmageed, Z. Y. A., & Sayed, K. A. E. (2023) · Marine Drugs · doi:10.3390/md21040215 · Cited by 11
The Link between miRNAs and PCKS9 in Atherosclerosis
Mačvanin, M., Gluvic, Z. M., Klisic, A. N., Manojlovic, M. S., Suri, J. S., Rizzo, M., & Isenović, E. R. (2023) · Current Medicinal Chemistry · doi:10.2174/0109298673262124231102042914 · Cited by 13
Piras, L., Zuccanti, M., Russo, P., Riccio, F., Agresti, A., Lustri, C., Dardani, D., Ferrera, A., Fiorentini, V., Tocci, G., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052502 · Cited by 11
Targeting metabolism of breast cancer and its implications in T cell immunotherapy
Zou, J., Mai, C., Lin, Z., Zhou, J., & Lai, G. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1381970 · Cited by 15
Li, C., Wang, W., Ma, S., Lo, L., Wu, C., Chang, W., Chen, Y., & Chen, T. (2024) · British Journal of Dermatology · doi:10.1093/bjd/ljae438 · Cited by 10
Self-citationScalambra, L., Ruzzi, F., Pittino, O. M., Semprini, M. S., Cappello, C., Angelicola, S., Palladini, A., Nanni, P., Goksøyr, L., Fougeroux, C. E., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06126-w · Cited by 10
Deciphering metabolic reprogramming of immune cells within the tumor microenvironment
Wang, Y., Chen, W., Wang, Z., Cai, S., Zhao, X., Jin, J., Gao, T., & Qu, J. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07069-y · Cited by 10
“Recent findings have revealed that PCSK9 inhibition synergizes with anti-PD-1 in melanoma, breast, and colon cancer models, supporting the combinatorial use of lipid-lowering agents with ICB [33].”
Liu, L., Hui, R., Zeng, T., Yang, X., Wu, Q., & Yang, T. (2022) · International Journal of General Medicine · doi:10.2147/ijgm.s355889 · Cited by 10
Effect of M2-like macrophages of the injured-kidney cortex on kidney cancer progression
Ishii, T., Mimura, I., Nagaoka, K., Naito, A., Sugasawa, T., Kuroda, R., Yamada, D., Kanki, Y., Kume, H., Ushiku, T., et al. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01255-3 · Cited by 10
“To evaluate the efficacy of anti-PD1 antibody in our model, 100 μg of mouse anti-PD1 antibodies (clone RMP1-14, BioXcell, Lebanon, NH, USA) or 100 μg of rat IgG2a isotype control (clone 2A3, BioXcell, Lebanon, NH, USA) were intraperitoneally injected four times every 2 days starting 7 days after tumor inoculation [81].”
MethodKondapalli, L., & Neilan, T. G. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab708 · Cited by 10
Osataphan, S. A., Awidi, M. A., Jan, Y. J., Gunturu, K. S., Sundararaman, S. K., Viray, H., Frankenberger, E., Mariano, M., O’Loughlin, L., Piper‐Vallillo, A. J., et al. (2024) · Lung Cancer · doi:10.1016/j.lungcan.2024.108023 · Cited by 9
Pecci, F., Cognigni, V., Giudice, G. C., Paoloni, F., Cantini, L., Saini, K. S., Abushukair, H. M., Naqash, A. R., Cortellini, A., Mazzaschi, G., et al. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.104654 · Cited by 9
PCSK9 in Vascular Aging and Age-Related Diseases
Tan, D., Yang, X., Yang, J., Fan, G., & Xiong, G. (2025) · Aging and Disease · doi:10.14336/ad.2024.1713 · Cited by 10
“Inhibition of PCSK9 enhances the expression of major histocompatibility complex class I (MHC I) proteins on tumor cell surfaces, facilitating significant intratumoral infiltration of cytotoxic T lymphocytes [163].”
Cholesterol metabolism: A strategy for overcoming drug resistance in tumors
Li, J., Guo, Y., Zhang, W., Xia, M. H., Liu, G., Sun, Y. P., Liu, C. X., & Zhong, J. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116974 · Cited by 10
Targeting lipid metabolism to enhance cancer immunotherapy
Zhao, D., Wu, L., & Li, Y. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189416 · Cited by 11
Cholesterol metabolism: a new checkpoint in cancer immunity
Zhao, L., Zheng, R., Liu, W., Li, X., Liu, H., Yin, H., Zhang, R., & Yang, A. (2025) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2025.11.003 · Cited by 13
Zhang, H., Xu, Q., Ye, M., Wu, X., Ren, Z., Qin, L., Tang, Z., Wang, G., Xiang, Q., & Liu, L. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.01.045 · Cited by 9
Wang, S., Wang, L., Li, H., et al. (2022) · Oral Diseases · doi:10.1111/odi.14456 · Cited by 9
PCSK9 inhibition: Not just LDL-Cholesterol knock down: A glimmer for cancer
Patrono, C., & Volpe, M. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab047 · Cited by 9
Farooq, H., Bien, H., Chang, V. T.-S., Becker, D. J., Park, Y.-H., & Bates, S. E. (2022) · Seminars in Oncology · doi:10.1053/j.seminoncol.2022.06.008 · Cited by 9
What Are the Roles of Proprotein Convertases in the Immune Escape of Tumors?
Mehranzadeh, E., Crende, O., Badiola, I., & García-Gallastegui, P. (2022) · Biomedicines · doi:10.3390/biomedicines10123292 · Cited by 9
“In accordance with some findings, it has been clarified that inhibiting PCSK9 may induce the infiltration of T lymphocytes in to the TME, subsequently provoking tumor cells to respond to immune checkpoint therapy [95].”
BackgroundInfluentialRada, M., Krzywoń, L., Kapelanski‐Lamoureux, A., Petrillo, S. K., Reynolds, A. R., Lazaris, A., Seidah, N. G., & Metrakos, P. P. (2022) · medRxiv · doi:10.1101/2022.10.16.22281153 · Cited by 9
“Moreover, Liu et al.28 have reported that evolocumab potentiated immune checkpoint therapy against various types of tumours in vivo.”
BackgroundChen, L., Du, Y., Qiao, H., Yang, L., Zhang, P., Wang, J., Zhang, C., Jiang, W., Xu, R., & Zhang, X. (2024) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2023.107517 · Cited by 9
Repurposing Two Old Friends to Fight Cancer: Caffeine and Statins
Stouth, D. W., Lebeau, P. F., & Austin, R. C. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-1066 · Cited by 8
A bibliometric analysis of PCSK9 inhibitors from 2007 to 2022
Luo, Q., Tang, Z., Wu, P., Chen, Z., Fang, Z., & Luo, F. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1218968 · Cited by 9
“In addition, PCSK9 inhibition enhances the sensitivity of tumors to immune checkpoint therapy (112).”
BackgroundPCSK9 Inhibitors and Anthracyclines: The Future of Cardioprotection in Cardio-Oncology
Repp, M. L., Edwards, M. D., Burch, C. S., Rao, A., & Chinyere, I. R. (2024) · Hearts · doi:10.3390/hearts5030027 · Cited by 8
“Corroborating their known pleiotropic effects, preclinical studies have demonstrated that PCSK9 inhibition synergistically enhances immunotherapy’s anti-tumor effects through LDL-receptor-independent pathways [76,77].”
BackgroundTargeting metabolic pathway enhance CAR-T potency for solid tumor
Li, W., Chen, J., & Guo, Z. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113412 · Cited by 9
Immuno-inflammatory mechanisms in cardio-oncology: new hopes for immunotargeted therapies
Miao, M., Liu, X., Zhang, H., & Dai, H. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1516977 · Cited by 10
Self-citationSong, Y., Jiang, Y., Guan, J., Jiang, J., Xu, M., Zhong, X., He, L.-N., Ren, Z.-Y., Liao, Y., Liu, F., et al. (2025) · Acta Pharmacologica Sinica · doi:10.1038/s41401-025-01541-7 · Cited by 8
“Moreover, PCSK9 inhibition can prevent MHC-I degradation in lysosomes, allowing MHC-I to return to cell membranes for appropriate antigen presentation [48].”
Self-citationZhang, C., Miao, Z., Xu, Y., Zhu, X., & Shi, T. (2025) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70789 · Cited by 7
Lipid-laden macrophages in atherosclerosis and cancer
Martínez-Campanario, M. C., Cortés, M., Han, L., Brischetto, A., Rivero-Soriano, P., Font-Díaz, J., Maurel, J., Andrés, V., & Postigo, A. A. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.09.007 · Cited by 9
Sun, P., Han, F., Li, X., Wu, C., Deng, T., He, J., Zhang, C., & Kuai, R. (2025) · Nature Communications · doi:10.1038/s41467-025-66630-x · Cited by 8
“Whilerecentstudieshaveshownthat targeting extracellular PCSK9 enhances tumor cell-surface MHC I stability 43 ,theroleofintracellularPCSK9inregulatinginnateimmunity has remained largely unexplored.”
Meningeal blood vessel blockage enhances anti-glioblastoma immunity
Gao, Y., Peng, Y., Cheng, J., Zhang, X., Zhong, J., Lu, C., Xing, X., Lai, Y., Sun, H., Zeng, X., et al. (2026) · Cell · doi:10.1016/j.cell.2025.12.045 · Cited by 10
Self-citationZhang, X., Ding, H., Deng, L.-F., Chen, G., Li, J., He, Z.-Y., Fu, L., Li, J., Jiang, F., Zhang, Z., et al. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1153986 · Cited by 8
“According to the available evidence, lipid-lowering medicines, such as statins, PARP inhibition, fenofibrate, and PCSK9, have been implied to have anti-tumor effects in several human malignancies, including ovarian cancer (68, 75, 76).”
BackgroundCediranib enhances the transcription of MHC-I by upregulating IRF-1
Zhang, J., Guo, H., Wang, L., Zheng, M., Kong, S., Wu, H., Zhao, L., Zhao, Q., Yang, X., He, Q., et al. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116036 · Cited by 8
The Biology and Clinical Implications of PCSK7
Sachan, V., Susan‐Resiga, D., Lam, K., & Seidah, N. G. (2024) · Endocrine Reviews · doi:10.1210/endrev/bnae031 · Cited by 9
Immunotherapeutic Strategies in Cancer and Atherosclerosis—Two Sides of the Same Coin
Nettersheim, F. S., Picard, F. S. R., Hoyer, F. F., & Winkels, H. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.812702 · Cited by 9
“However, in a recent study PCSK9 inhibition could potentiate anti-tumor immune responses and thus substantially reduced tumor growth in murine cancer models (226), which was independent of cholesterol-lowering.”
BackgroundInfluentialShu, L., Liu, S., & Tao, Y. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.902353 · Cited by 8
“Meanwhile, inhibiting PCSK9 effectively enhances PD-1 inhibitor therapy for cancers (58).”
BackgroundAnimal Models of Hepatocellular Carcinoma: Current Applications in Clinical Research
Fornari, F., Giovannini, C., Piscaglia, F., & Gramantieri, L. (2022) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s347946 · Cited by 7
“Mechanisms of action seem independent of the cholesterol regulation, rather relying on the recycling of MHC I molecules for degradation to lysosomes.(48) On a different wavelength, a preclinical study reported that injection of DEN early in life in PCSK9 KO mice leads to significant NASH-HCC development, confirming th…”
BackgroundBellino, M., Galasso, G., Silverio, A., Tedeschi, M., Formisano, C., Romei, S., Esposito, L., Cancro, F. P., Vassallo, M. G., Accarino, G., et al. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082922 · Cited by 10
“Mutations causing a decrease in PCSK-9 activity are associated with inhibition of the progression of colorectal and breast cancer, mainly, but not only, through a decrease in LDL-C concentration [36].”
BackgroundTrends of High-Impact Studies in Pharmacology and Pharmacy: A Cross-Sectional Study
Chen, L., Yang, Y., Fan, J., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.726668 · Cited by 8
“Cancer treatment is the most prominent topic for high-impact studies in thisfield (Jin et al., 2021; Li et al., 2020; Liu et al., 2020).”
BackgroundRada, M., Reynolds, A. R., Lazaris, A., Seidah, N. G., & Metrakos, P. P. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.29.542731 · Cited by 8
Zhang, N., Gu, T., Hu, S., et al. (2024) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwae368 · Cited by 7
MCRS1 sensitizes T cell–dependent immunotherapy by augmenting MHC-I expression in solid tumors
Li, X., Han, Y., Jin, Z., Jiang, K., Xue, K., Wang, J., Qian, Y., Xiang, Q., Zhu, S., Yan, R., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20240959 · Cited by 8
“Concordantly, targeting the MHC-I degradation pathways has been found to augment antigen presentation and sensitize tumor clearing by T cells in multiple tumor models (Chen et al., 2023; Liu et al., 2020; Yamamoto et al., 2020b).”
PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis
Zhang, Y., Su, W., Ji, X., Zhou, Y., Guan, Q., Pang, Y., Zhong, L., Wang, Y., & Xiang, J. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07690-1 · Cited by 7
Martín, A., Daniela Gerovska, D., Araúzo-Bravo, M. J., García-Escudero, M. D., García, H. G., Bañares, I., Fontal, N., Siegfried, G., Évrard, S., Pernot, S., et al. (2025) · Cancers · doi:10.3390/cancers17121977 · Cited by 7
“It also impairs immune recognition by downregulating major histocompatibility complex class I (MHC-I) expression on tumor cells, facilitating immune evasion [20,21].”
Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation
Xiao, J., Li, Z., Ding, Y., Zhu, K., Zheng, Z., Zhang, Y., Weng, J., Wang, F., Zhang, Y., Zeng, S., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.11.016 · Cited by 8
Qin, L., Shi, L., Wang, Y., Yu, H., Du, Z., Chen, M., Cai, Y., Cao, Y., Deng, S., Wang, J., et al. (2024) · Cancers · doi:10.3390/cancers16040713 · Cited by 7
“Simultaneously, PCSK9 plays a crucial role in regulating MHC I levels on cell surfaces, influencing immune infiltration within tumors, and responding to immune checkpoint therapy [10].”
BackgroundInfluentialImpact of Lipid-lowering Therapy on Cancer Risk: A Narrative Review
Pasha, R., Bashir, B., Omed, D., Adam, S., Kamath, A., Elhofy, A., Ferdousi, M., Azmi, S., & Soran, H. (2024) · Clinical Therapeutics · doi:10.1016/j.clinthera.2024.03.004 · Cited by 7
Ye, D., Zhou, S. Y., Dai, X., Xu, H., Tang, Q., Huang, H., & Bi, F. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189161 · Cited by 8
Effects of PCSK9 inhibitors on cancer, diabetes, and cardiovascular diseases
Nejabat, M., Hadizadeh, F., Almahmeed, W., & Sahebkar, A. (2025) · Drug Discovery Today · doi:10.1016/j.drudis.2025.104316 · Cited by 7
Li, X., Yuan, P., Yang, H., Zong, X., Yang, C., Chen, X., Li, Y., Yan, X., Wen, Y., Zhu, T., et al. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202300921 · Cited by 7
Zhao, J., Wang, R., Song, L., Han, H., Wang, P., Zhao, Y., Zhang, Y., & Zhang, H. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1295412 · Cited by 7
Immune Checkpoint Inhibitors and Their Cardiovascular Adverse Effects
Paluri, R. K., Pulipati, Y., & Regalla, D. K. R. (2023) · Oncology Reviews · doi:10.3389/or.2023.11456 · Cited by 8
“Similar to statins, PCSK-9 inhibitors also demonstrated synergistic action with PD-1 inhibitors by suppressing tumor growth in mouse models [96].”
Advances in spatial multi-omics in tumors
Wang, J., Alhaskawi, A., Dong, Y., Tian, T., Abdalbary, S. A., & Lü, H. (2024) · Tumori Journal · doi:10.1177/03008916241271458 · Cited by 6
“…on special immune structures of tumor microenvironment using spatial omics have derived various therapeutic strategies, consisting of promoting 77,78 or preventing 79 immune cell infiltration into designated areas of the tumor microenvironment, anti-angiogenesis or oxygenation, 80,81 and…”
Yuan, C., Hu, C.-P., Zhou, H.-Y., Liu, W., Lai, W.-J., Liu, Y.-F., Yin, Y., Li, G.-B., & Zhang, R. (2025) · Neoplasia · doi:10.1016/j.neo.2025.101160 · Cited by 7
“Blocking PCSK9 has been shown to enhance the anti-tumor activity of CD8 + T cells [12 – 14].”
Risk Factors and Prevention of Cancer and CVDs: A Chicken and Egg Situation
Abrignani, M. G., Lucà, F., Abrignani, V., Nucara, M., Grosseto, D., Lestuzzi, C., Mistrangelo, M., Passaretti, B., Rao, C. M., & Parrini, I. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14093083 · Cited by 6
“Additionally, the long-term reduction of systemic LDL-C levels may influence cancer cell proliferation, given the critical role of cholesterol in membrane synthesis and intracellular signaling [179,182].”
Porcheron, C., Dévéhat, M. L., Roubtsova, A., Bayat, H., Evagelidis, A., Jafarzadeh, L., Sachan, V., Labrecque, N., Holder, A. F., Susan‐Resiga, D., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-011364 · Cited by 6
“1 2 Additionally, PCSK9 is implicated in the activation of CD8 + T cells through two mechanisms: the degradation of the major histocompatibility complex-I (MHC-I), 12 responsible for antigen presentation, and the increased signaling of the T-cell receptor (TCR)/LDLR receptor complex.”
Li, Y., Zhou, S., Fu, W., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2415100122 · Cited by 6
Cholesterol metabolism regulates macrophage function and inflammation-related diseases
Xiao, J., Wang, S., Jin, M., Wei, B., & Wang, H. (2025) · Trends in Cell Biology · doi:10.1016/j.tcb.2025.10.003 · Cited by 8
Sun, M., Wang, Q., Wu, L. J., Zhang, Y., Ren, J., & Qu, X. (2025) · ACS Nano · doi:10.1021/acsnano.5c14098 · Cited by 7
Cathepsin-D-mediated MHC class I degradation contributes to immune evasion in colorectal cancer
Zhan, W., Fu, Y., Liu, Y., Cai, R., Bai, F., Guo, C., Cheng, Y., Wu, Z., Qin, G., Xie, Y., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102534 · Cited by 7
Adverse Reactions to Evolocumab: Analysis of Real-World Data from EudraVigilance
Calapai, F., Mannucci, C., Currò, M., Cardia, L., Esposito, E., Calapai, G., & Ammendolia, I. (2024) · Pharmaceuticals · doi:10.3390/ph17030364 · Cited by 7
“Moreover, PCSK9 seems to be involved in the phys-iopathology underlying the development of pancreatic cancer and Alzheimer’s disease [2,3].”
BackgroundLi, J., Yang, Z., Wang, T., Li, M., Wu, X., Fu, X., Yang, C., Li, Y., Wang, X., Lan, Z., et al. (2024) · BMC Cancer · doi:10.1186/s12885-024-12434-z · Cited by 6
“Recent findings suggest that inhibiting PCSK9 enhances the tumor’s response to immune checkpoint therapy, and both genetic and pharmacological reduction of PCSK9 can suppress tumor growth [22].”
BackgroundThe effect of smoking on tumor immunoediting: Friend or foe?
Jiang, Y., & Li, H. (2024) · Tobacco Induced Diseases · doi:10.18332/tid/189302 · Cited by 6
“Studies have shown that the expression of the PCSK9 gene activates lysosomes and promotes the degradation of MHC I molecules on the cell surface, thereby reducing tumor immune cell infiltration and increasing the possibility of immune escape 68 .”
BackgroundZhang, A. M. C., Ziogos, E., Harb, T., Gerstenblith, G., & Leucker, T. M. (2024) · European Journal of Clinical Investigation · doi:10.1111/eci.14273 · Cited by 6
“69”
Kristoff, T. J., Evans, S., Nayi, P., Abousaud, M. I., Goyal, S., Liu, Y., Shin, D. M., Steuer, C. E., Saba, N. F., & Schmitt, N. C. (2025) · Cancer Medicine · doi:10.1002/cam4.70718 · Cited by 6
Immune checkpoint inhibitors and myocardial infarction
Juhász, V., Suero‐Abreu, G. A., & Neilan, T. G. (2025) · Journal of Thrombosis and Thrombolysis · doi:10.1007/s11239-025-03081-7 · Cited by 7
Muramatsu, M., Osawa, T., Miyamura, Y., Nakagawa, S., Tanaka, T., Kodama, T., Aburatani, H., Sakai, J., Ryeom, S. W., & Minami, T. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100697 · Cited by 6
“Most recently, PCSK9 inhibition also enhanced cytotoxic T cell function with immune-checkpoint therapy against tumors (31).”
BackgroundQiu, G., Zhang, L., Gu, Z., Ren, H., Du, Y., Li, Z., & Wang, C. (2021) · Medical Science Monitor · doi:10.12659/msm.931868 · Cited by 6
“Recently, it was discovered that the PCSK9 protein, which regulates CHO metabolism, has immune regulation functions for tumors, and that inhibiting its activity can promote the intratumoral infiltration of cytotoxic T cells and thereby enhance the effect of immunotherapy [28].”
BackgroundRegulation of secretory pathway kinase or kinase-like proteins in human cancers
Du, S., Zhu, C. Y., Ren, X., Chen, X., Cui, X., & Guan, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.942849 · Cited by 6
“This attenuation depends on cytotoxic T cells and boosts the response of tumors to immune checkpoint therapy targeted at the checkpoint protein PD1 through a mechanism independent of PCSK9’s cholesterol-regulating functions (67).”
BackgroundDuan, H., Shi, Y. X., Zhang, Q., Shi, X., Zhang, Y., Liu, J., & Zhang, Y. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1335489 · Cited by 6
“Remarkably, PCSK9i demonstrates potential pleiotropic effects, including the improvement of tumor response to immune checkpoint , reduction in platelet activation and thrombosis, and the attenuation of cell apoptosis (18 – 20).”
BackgroundTan, S., Nelson, A. J., Muthalaly, R. G., Ramkumar, S., Hamilton, J., Nerlekar, N., Segelov, E., & Nicholls, S. J. (2024) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwae204 · Cited by 6
miR-181d-5p ameliorates hypercholesterolemia by targeting PCSK9
Wang, Y., Li, F., Gao, X., Yu, H., Du, Z., Li, L., Yunhui, D., Hu, C., & Qin, Y. (2024) · Journal of Endocrinology · doi:10.1530/joe-23-0402 · Cited by 5
Self-citationThe biological relevance of PCSK9: when less is better…
Mbikay, M., & Chrétien, M. (2022) · Biochemistry and Cell Biology · doi:10.1139/bcb-2021-0540 · Cited by 6
Ruscica, M., Macchi, C., Gandini, S., Macis, D., Guerrieri‐Gonzaga, A., Aristarco, V., Serrano, D., Lazzeroni, M., Rizzuto, A. S., Gaeta, A., et al. (2024) · Cancers · doi:10.3390/cancers16071411 · Cited by 5
“Indeed, PCSK9 triggers the degradation of the Major Histocompatibility Complex 1 (MHC-I) receptor [13].”
BackgroundImmune checkpoint inhibitors: Unravelling atherosclerotic cardiovascular risk
Gray, R., Manisty, C., Cheng, R. K.-H., Dastidar, A. G., Mamas, M. A., & Ghosh, A. K. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2025.119147 · Cited by 7
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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