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Peer-reviewedCC BY-NC 4.0Journal for ImmunoTherapy of Cancer

SIRPA drives T cell apoptosis to promote immune evasion in hepatocellular carcinoma

  • Xue Zhang1,2,3
  • Liying Ren1,2,3,4
  • Pu Chen1,2,3,5
  • Kangjian Deng6
  • Xingwang Xie1,2,3,7
  • Placide Sesonga8
  • Shaoping She1,2,3
  • Xu Cong1,2,3
  • Ran Fei1,2,3
  • Weijia Liao9
  • Hongsong Chen1,2,3,10
  • Dongbo Chen1,2,3
10 affiliations
  1. 1Peking University People’s Hospital, Beijing, China
  2. 2Peking University Hepatology Institute, Beijing, China
  3. 3Infectious Disease and Hepatology Center, Peking University People’s Hospital, Beijing, China
  4. 4Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, China
  5. 5Department of Gastroenterology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
  6. 6Department of Vascular Thyroid Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
  7. 7Corregene Biotechnology Co., Ltd, Beijing, China
  8. 8Canada’s Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada
  9. 9Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China
  10. 10Peking University Third Hospital, Beijing, China
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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.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026sirpa,
  title = {{SIRPA drives T cell apoptosis to promote immune evasion in hepatocellular carcinoma}},
  author = {Xue Zhang and Liying Ren and Pu Chen and Kangjian Deng and Xingwang Xie and Placide Sesonga and Shaoping She and Xu Cong and Ran Fei and Weijia Liao and Hongsong Chen and Dongbo Chen},
  journal = {Journal for ImmunoTherapy of Cancer},
  year = {2026},
  month = oct,
  doi = {10.1136/jitc-2026-015539},
  url = {https://doi.org/10.1136/jitc-2026-015539},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - SIRPA drives T cell apoptosis to promote immune evasion in hepatocellular carcinoma
AU  - Xue Zhang
AU  - Liying Ren
AU  - Pu Chen
AU  - Kangjian Deng
AU  - Xingwang Xie
AU  - Placide Sesonga
AU  - Shaoping She
AU  - Xu Cong
AU  - Ran Fei
AU  - Weijia Liao
AU  - Hongsong Chen
AU  - Dongbo Chen
PY  - 2026
DA  - 2026/10/23
JO  - Journal for ImmunoTherapy of Cancer
DO  - 10.1136/jitc-2026-015539
UR  - https://doi.org/10.1136/jitc-2026-015539
AB  - 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.
SN  - 2051-1426
ER  -