{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "The University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Department 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",
    "Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital Affiliated to Southern Medical University, Guangzhou, Guangdong, China",
    "1University of Tasmania, Sandy Bay, TAS, Australia",
    "The 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",
    "Medical Research Institute, Guangdong Provincial People`s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
    "3 School of Medicine, South China University of Technology, Guangzhou, Guangdong, China",
    "School of Medicine, South China University of Technology, Guangzhou, Guangdong, China",
    "College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xi Chen"
    },
    {
      "affs": [
        1
      ],
      "name": "Yong Li"
    },
    {
      "affs": [
        2
      ],
      "name": "Xin Guo"
    },
    {
      "affs": [
        3
      ],
      "name": "Renjie Li"
    },
    {
      "affs": [
        4
      ],
      "name": "Yuhan Zhang"
    },
    {
      "affs": [
        5
      ],
      "name": "Baijin Xia"
    },
    {
      "affs": [
        6
      ],
      "name": "Huolun Feng"
    },
    {
      "affs": [
        7
      ],
      "name": "Zhihui Xi"
    },
    {
      "affs": [
        8
      ],
      "name": "Jianlong Zhou"
    },
    {
      "affs": [
        2
      ],
      "name": "Yiheng Xing"
    },
    {
      "affs": [
        2
      ],
      "name": "Qiming Fan"
    },
    {
      "affs": [
        2
      ],
      "name": "Kunling Chen"
    },
    {
      "affs": [
        2
      ],
      "name": "Yuyuan Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b669hpcpx3m78.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-016573",
  "fulltext_url": "https://jitc.bmj.com/content/14/11/e016573.full",
  "id": "b669hpcpx3m78",
  "issns": [
    "2051-1426"
  ],
  "landing_url": "https://doi.org/10.1136/jitc-2026-016573",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC254-282"
    ],
    [
      "openalex",
      "2403|Immune cells in cancer"
    ]
  ],
  "openalex": "W7225375031",
  "pdf_url": "https://jitc.bmj.com/content/14/11/e016573.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-09",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/b669hpcpx3m78.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T14:21:36Z",
      "native_id": "00782c29e6ff4befbf50c667f0526b0f",
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      "url": "https://doi.org/10.1136/jitc-2026-016573"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune cells in cancer",
      "subfield": "immunology"
    }
  ],
  "title": "Multi-omics reveals PCSK9 induces precursor-like macrophage M2 polarization to exacerbate immunosuppression in peritoneal metastasis",
  "title_text": "Multi-omics reveals PCSK9 induces precursor-like macrophage M2 polarization to exacerbate immunosuppression in peritoneal metastasis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T14:21:36Z",
  "url": "https://research.draconitic.com/paper/b669hpcpx3m78",
  "venue": "Journal for ImmunoTherapy of Cancer",
  "versions": []
}