A CD4+ T lymphocyte–specific TCR/GSDMD/IL-2 axis facilitates antitumor immunity
Yihan Yao, … , Wanqiang Sheng, Xiaojian Wang
Yihan Yao, … , Wanqiang Sheng, Xiaojian Wang
Published August 1, 2025
Citation Information: J Clin Invest. 2025;135(15):e191119. https://doi.org/10.1172/JCI191119.
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Research Article Immunology Oncology

A CD4+ T lymphocyte–specific TCR/GSDMD/IL-2 axis facilitates antitumor immunity

Abstract

Gasdermin (GSDM) family proteins mediate tumor pyroptosis and impact cancer progression, but other than that, their involvement in the tumor immune microenvironment remains largely unknown. Here, we show that activation of GSDMD in human tumor specimens mainly occurs in tumor-infiltrating leukocytes. Significantly, GSDMD deficiency or its inactivation in CD4+ T cells disabled CD8+ T cell–mediated antitumor immunity and caused tumor outgrowth in mice. Further study uncovered that, via inducing IL-2 production, GSDMD was required for CD4+ T cells to provide help to CD8+ T cell function. Mechanistically, GSDMD was cleaved by TCR stimulation–activated caspase-8 to form GSDMD-N pores, which enhanced Ca2+ influx for IL-2 induction. Moreover, GSDMD activation and function were conserved in human CD4+ T cells and associated with favorable prognosis and improved response to anti–PD-1 immunotherapy in colonic and pancreatic cancer. We believe this study identifies a new nonpyroptotic role of GSDMD in tumor immunity, proposing GSDMD as a potential target for cancer immunotherapy.

Authors

Yihan Yao, Lingling Wang, Weiqin Jiang, Ning Wang, Mengjie Li, Wenlong Lin, Ting Zhang, Wanqiang Sheng, Xiaojian Wang

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Figure 4

GSDMD in CD4+ T cells promotes antitumor immunity by increasing IL-2 production.

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GSDMD in CD4+ T cells promotes antitumor immunity by increasing IL-2 pro...
(A) Levels of the indicated cytokines in supernatant of MC38 tumors isolated from Gsdmdfl/fl and Gsdmdfl/fl CD4cre mice, determined by LEGENDplex (BioLegend) (n = 8 per group). (B–E) Quantifications of IL-2 by ELISA in supernatant of MC38 tumors isolated from WT (n = 6) and Gsdmd–/– (n = 9) mice (B), Gsdmdfl/fl (n = 10) and Gsdmdfl/fl CD4cre (n = 8) mice (C), WT mice treated with DMSO or DSF (D, n = 5 per group), or WT (n = 4) and Gsdmd–/– (n = 8) mice treated with CD8α-depleting antibodies (E). (F–H) Percentages of IL-2–expressing CD8+ and CD4+ TILs in MC38 tumors implanted in WT (n = 10) and Gsdmd–/– (n = 9) mice (F), WT mice treated with DMSO or DSF (n = 6 per group) (G), or Gsdmdfl/fl (n = 10) and Gsdmdfl/fl CD4cre (n = 8) mice (H), analyzed by flow cytometry. (I and J) Tumor growth curves (left) and tumor weights (right) of WT and Gsdmd–/– mice inoculated with MC38 tumor cells and treated with recombinant IL-2 (I, n = 11 per group). Percentages of IFN-γ–expressing CD8+ TILs were assessed (J). (K and L) Tumor growth curves (left) and tumor weights (right) of MC38 tumors in WT (n = 10) and Gsdmd–/– (n = 12) mice treated with FK506 (K). Percentages of IFN-γ–expressing TILs were assessed (L). (M and N) Tumor growth curves (left) and tumor weights (right) of MC38 tumors in WT mice cotreated with DMSO or DSF and FK506 (M, n = 10 per group). Percentages of IFN-γ–expressing TILs were assessed (N). Data are presented as mean ± SEM and are representative of at least 2 independent experiments (A–N). *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant; as determined by 2-way ANOVA for tumor growth curves or unpaired 2-tailed Student’s t tests for others.