Multi-omics reveals PCSK9 induces precursor-like macrophage M2 polarization to exacerbate immunosuppression in peritoneal metastasis
9 affiliations
- 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 2Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Beijing, China
- 3Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital Affiliated to Southern Medical University, Guangzhou, Guangdong, China
- 41University of Tasmania, Sandy Bay, TAS, Australia
- 5The Affiliated Wuxi People`s Hospital of Nanjing Medical University, Wuxi People`s Hospital, Wuxi Medical Center & Department of Immunology, School of Basic Medical Sciences, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
- 6Medical Research Institute, Guangdong Provincial People`s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- 73 School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- 8School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- 9College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
Abstract
Background Peritoneal metastasis (PM) is characterized by an immunosuppressive tumor microenvironment (TME), therapeutic resistance, and poor clinical outcomes. However, the key mediators driving immune suppression in PM remain largely unknown. This study aimed to identify the central regulators of the immunosuppressive TME and evaluate their therapeutic potential.Methods Integrated analyses were performed using single-cell RNA sequencing data from 19 clinical samples together with multiple bulk RNA-seq datasets to characterize the immune landscape of PM. Mechanistic studies were conducted to investigate the role of tumor-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) in macrophage polarization and T-cell function. The therapeutic effects of PCSK9 inhibition, alone or in combination with anti- programmed cell death protein 1 (PD-1) therapy following chemotherapy, were evaluated in preclinical models. In addition, the efficacy of anti-PCSK9 therapy delivered via pressurized intraperitoneal aerosol chemotherapy (PIPAC) was validated in a rabbit model.Results Integrated transcriptomic analyses identified precursor-like macrophage M2 polarization as a central driver of the immunosuppressive TME in PM. Mechanistically, tumor-derived PCSK9 promoted M2 polarization of precursor-like macrophages through the nuclear factor kappa-B (NF-κB)-interleukin-10 (IL-10) signaling axis, leading to impaired T-cell function. PCSK9 inhibition reversed macrophage polarization and reprogrammed the TME toward an antitumor phenotype by enhancing T-cell activation and recruitment via the Cxcl16-Cxcr6 axis. In our exploratory preclinical experiments, sequential chemotherapy followed by combined anti-PCSK9 and anti-PD-1 therapy demonstrated schedule-dependent therapeutic benefit. Furthermore, anti-PCSK9 therapy delivered through PIPAC showed therapeutic efficacy in a rabbit model.Conclusions PCSK9 is a key mediator of immune suppression in PM by promoting immunosuppressive macrophage polarization and T-cell dysfunction. Targeting PCSK9 remodels the TME and enhances antitumor immunity, supporting PCSK9 inhibition as a promising therapeutic strategy, particularly in combination with chemotherapy and immune checkpoint blockade for the treatment of PM.
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BibTeX
@article{chen2026multiomics,
title = {{Multi-omics reveals PCSK9 induces precursor-like macrophage M2 polarization to exacerbate immunosuppression in peritoneal metastasis}},
author = {Xi Chen and Yong Li and Xin Guo and Renjie Li and Yuhan Zhang and Baijin Xia and Huolun Feng and Zhihui Xi and Jianlong Zhou and Yiheng Xing and Qiming Fan and Kunling Chen and Yuyuan Zhang},
journal = {Journal for ImmunoTherapy of Cancer},
year = {2026},
month = nov,
doi = {10.1136/jitc-2026-016573},
url = {https://doi.org/10.1136/jitc-2026-016573},
note = {CC BY},
}
RIS
TY - JOUR
TI - Multi-omics reveals PCSK9 induces precursor-like macrophage M2 polarization to exacerbate immunosuppression in peritoneal metastasis
AU - Xi Chen
AU - Yong Li
AU - Xin Guo
AU - Renjie Li
AU - Yuhan Zhang
AU - Baijin Xia
AU - Huolun Feng
AU - Zhihui Xi
AU - Jianlong Zhou
AU - Yiheng Xing
AU - Qiming Fan
AU - Kunling Chen
AU - Yuyuan Zhang
PY - 2026
DA - 2026/11/09
JO - Journal for ImmunoTherapy of Cancer
DO - 10.1136/jitc-2026-016573
UR - https://doi.org/10.1136/jitc-2026-016573
AB - Background Peritoneal metastasis (PM) is characterized by an immunosuppressive tumor microenvironment (TME), therapeutic resistance, and poor clinical outcomes. However, the key mediators driving immune suppression in PM remain largely unknown. This study aimed to identify the central regulators of the immunosuppressive TME and evaluate their therapeutic potential.Methods Integrated analyses were performed using single-cell RNA sequencing data from 19 clinical samples together with multiple bulk RNA-seq datasets to characterize the immune landscape of PM. Mechanistic studies were conducted to investigate the role of tumor-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) in macrophage polarization and T-cell function. The therapeutic effects of PCSK9 inhibition, alone or in combination with anti- programmed cell death protein 1 (PD-1) therapy following chemotherapy, were evaluated in preclinical models. In addition, the efficacy of anti-PCSK9 therapy delivered via pressurized intraperitoneal aerosol chemotherapy (PIPAC) was validated in a rabbit model.Results Integrated transcriptomic analyses identified precursor-like macrophage M2 polarization as a central driver of the immunosuppressive TME in PM. Mechanistically, tumor-derived PCSK9 promoted M2 polarization of precursor-like macrophages through the nuclear factor kappa-B (NF-κB)-interleukin-10 (IL-10) signaling axis, leading to impaired T-cell function. PCSK9 inhibition reversed macrophage polarization and reprogrammed the TME toward an antitumor phenotype by enhancing T-cell activation and recruitment via the Cxcl16-Cxcr6 axis. In our exploratory preclinical experiments, sequential chemotherapy followed by combined anti-PCSK9 and anti-PD-1 therapy demonstrated schedule-dependent therapeutic benefit. Furthermore, anti-PCSK9 therapy delivered through PIPAC showed therapeutic efficacy in a rabbit model.Conclusions PCSK9 is a key mediator of immune suppression in PM by promoting immunosuppressive macrophage polarization and T-cell dysfunction. Targeting PCSK9 remodels the TME and enhances antitumor immunity, supporting PCSK9 inhibition as a promising therapeutic strategy, particularly in combination with chemotherapy and immune checkpoint blockade for the treatment of PM.
SN - 2051-1426
ER -