{
  "abstract": "Background Immune checkpoint inhibitors provide limited clinical benefit in advanced hepatocellular carcinoma (HCC), highlighting the need to identify additional mechanisms of tumor immune evasion.Methods We performed genome-scale CRISPR-Cas9 knockout library screening to identify genes associated with T cell apoptosis and identified differentially expressed genes in tumor-infiltrating lymphocytes from HCC patients following high-dose interleukin 2 stimulation. Integrative analysis identified signal regulatory protein alpha (SIRPA) as a candidate regulator of T cell apoptosis. SIRPA was functionally validated in vivo and in vitro using Sirpα-/- mice and primary human T cells.Results In vitro, SIRPA deficiency significantly reduced apoptosis in both human and murine T cells, whereas SIRPA overexpression promoted apoptosis. In vivo, T cell-intrinsic loss of Sirpα markedly suppressed tumor growth, and even haploinsufficiency was sufficient to confer a notable antitumor effect. Following macrophage depletion, Sirpα-/- mice exhibited increased frequencies of functional CD8+ T cells in peripheral blood and tumor tissues, accompanied by elevated granzyme B expression, indicating that Sirpα deficiency confers resistance to apoptosis in T cells. Functionally, SIRPA overexpression impaired the cytotoxic activity of TCR-engineered T cells, whereas adoptive transfer of Sirpα-deficient T cells enhanced tumor control. Mechanistically, SIRPA overexpression activated SHP1, leading to inhibition of the PI3K/AKT/FOXO1 signaling pathway, and upregulation of EGR4. Elevated EGR4 interacted with FOXO1 to regulate the Bim/Bcl-2/Bax axis, thereby promoting T cell apoptosis and facilitating tumor immune evasion.Conclusions SIRPA functions as a previously unrecognized intrinsic regulator of T cell apoptosis in HCC. Targeting SIRPA may enhance anti-tumor immunity by preventing T cell apoptosis, representing a promising immunotherapeutic strategy.",
  "abstract_shown": true,
  "affiliations": [
    "Peking University People’s Hospital, Beijing, China",
    "Peking University Hepatology Institute, Beijing, China",
    "Infectious Disease and Hepatology Center, Peking University People’s Hospital, Beijing, China",
    "Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, China",
    "Department of Gastroenterology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China",
    "Department of Vascular Thyroid Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China",
    "Corregene Biotechnology Co., Ltd, Beijing, China",
    "Canada’s Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada",
    "Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China",
    "Peking University Third Hospital, Beijing, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Xue Zhang",
      "orcid": "0009-0008-2240-9081"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Liying Ren",
      "orcid": "0000-0003-3624-5483"
    },
    {
      "affs": [
        0,
        1,
        2,
        4
      ],
      "name": "Pu Chen"
    },
    {
      "affs": [
        5
      ],
      "name": "Kangjian Deng"
    },
    {
      "affs": [
        0,
        1,
        2,
        6
      ],
      "name": "Xingwang Xie"
    },
    {
      "affs": [
        7
      ],
      "name": "Placide Sesonga"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Shaoping She"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Xu Cong"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Ran Fei"
    },
    {
      "affs": [
        8
      ],
      "name": "Weijia Liao"
    },
    {
      "affs": [
        0,
        1,
        2,
        9
      ],
      "name": "Hongsong Chen"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Dongbo Chen",
      "orcid": "0000-0001-5173-6999"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ek73hp1sr86re.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-015539",
  "fulltext_url": "https://jitc.bmj.com/content/14/10/e015539.full",
  "id": "ek73hp1sr86re",
  "issns": [
    "2051-1426"
  ],
  "landing_url": "https://doi.org/10.1136/jitc-2026-015539",
  "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"
    ],
    [
      "lcc",
      "RC254-282"
    ],
    [
      "openalex",
      "2403|Phagocytosis and Immune Regulation"
    ]
  ],
  "openalex": "W7223273354",
  "pdf_url": null,
  "pmcid": "PMC13711587",
  "pmid": "42919623",
  "published": "2026-10-23",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/ek73hp1sr86re.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:44:21Z",
      "native_id": "3c89323e15e14c5f84e99b4c30357bd2",
      "source": "doaj",
      "url": "https://doi.org/10.1136/jitc-2026-015539"
    },
    {
      "first_seen": "2026-10-31T12:22:20Z",
      "native_id": "PMC13711587",
      "source": "pmc",
      "url": "https://doi.org/10.1136/jitc-2026-015539"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Phagocytosis and Immune Regulation",
      "subfield": "immunology"
    }
  ],
  "title": "SIRPA drives T cell apoptosis to promote immune evasion in hepatocellular carcinoma",
  "title_text": "SIRPA drives T cell apoptosis to promote immune evasion in hepatocellular carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:20Z",
  "url": "https://research.draconitic.com/paper/ek73hp1sr86re",
  "venue": "Journal for ImmunoTherapy of Cancer",
  "versions": []
}