{
  "abstract": "Background: Acquired resistance (AR) represents a major obstacle to immune checkpoint inhibitor (ICI) therapy in lung cancer. However, its underlying mechanisms and reversal strategies remain unclear.\n\nMethods: In this study, we analyzed paired tumor specimens from patients with AR to anti-programmed cell death protein 1 (PD-1) therapy and used mouse AR models, together with transcriptomic and metabolomic analyses, to investigate resistance mechanisms in lung cancer.\n\nResults: We identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as a key mediator of AR to anti-PD-1 therapy that suppresses CD8+ T-cell function by reprogramming cystine metabolism in the tumor microenvironment. Mechanistically, PCSK9 interacts with KEAP1 (kelch-like ECH-associated protein 1) and facilitates its lysosomal degradation, leading to upregulation of the cystine transporter SLC7A11 in tumor cells. Elevated SLC7A11 enhances cystine uptake by tumor cells, limiting its availability for CD8+ T cells and impairing their effector function. Furthermore, we demonstrate that PCSK9 upregulation in resistant tumors is induced by interferon-γ via the JAK1/2–STAT1 signaling axis. Importantly, inhibition of PCSK9 alleviates tumor-driven cystine competition, restores CD8+ T-cell function, and resensitizes resistant tumors to anti-PD-1 therapy.\n\nConclusions: These findings uncover a tumor-intrinsic immunometabolic mechanism of AR, wherein PCSK9 drives cystine competition between tumor cells and CD8+ T cells and highlight PCSK9 as a potential metabolic checkpoint for overcoming AR in immune checkpoint inhibitor therapy.",
  "abstract_shown": true,
  "affiliations": [
    "Shanghai Lung Cancer Center, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China",
    "Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China",
    "Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China",
    "Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Guangling Jie",
      "orcid": "0000-0002-4845-6280"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhengqi Cao"
    },
    {
      "affs": [
        0
      ],
      "name": "Jingze Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenqing Lu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaokuan Zhu"
    },
    {
      "affs": [
        0
      ],
      "name": "Ziming Li"
    },
    {
      "affs": [
        2
      ],
      "name": "Ying Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Shun Lu",
      "orcid": "0000-0001-8833-7262"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Liliang Xia"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/expxpdqwn7fq3.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-015974",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13711557/",
  "id": "expxpdqwn7fq3",
  "issns": [
    "2051-1426"
  ],
  "landing_url": "https://doi.org/10.1136/jitc-2026-015974",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "1506"
    ],
    [
      "heading",
      "2434"
    ],
    [
      "heading",
      "Basic and Translational Cancer Immunology"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7223003928",
  "pdf_url": null,
  "pmcid": "PMC13711557",
  "pmid": "42901717",
  "published": "2026-10-20",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/expxpdqwn7fq3.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:22:19Z",
      "native_id": "PMC13711557",
      "source": "pmc",
      "url": "https://doi.org/10.1136/jitc-2026-015974"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "PCSK9 drives acquired resistance to anti-PD-1 immunotherapy through cystine metabolic reprogramming in lung cancer",
  "title_text": "PCSK9 drives acquired resistance to anti-PD-1 immunotherapy through cystine metabolic reprogramming in lung cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:19Z",
  "url": "https://research.draconitic.com/paper/expxpdqwn7fq3",
  "venue": "Journal for Immunotherapy of Cancer",
  "versions": []
}