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<p>The limited success of current immunotherapies emphasizes the need for new targets and combination treatments. V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target in cancer immunotherapy, but its regulatory mechanism is poorly understood. Through CRISPR knockout screening and proteomic analysis, we identify tripartite motif containing 25 (TRIM25) as a positive regulator for VISTA largely through antagonizing its degradation signaling. Moreover, ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, leading to VISTA stabilization. A VISTA-derived phospho-peptide competitively disrupts TRIM25–VISTA interaction, thereby reducing VISTA expression and potentiating the anti-tumor efficacy of PD-1/PD-L1 blockade. Moreover, single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8<sup>+</sup> T cells are increased in mice with T cell-specific knockout of <i>Trim25</i>. Of note, genetic ablation of <i>Trim25</i> in T cells not only improves anti-PD-L1 immunotherapy, but also significantly ameliorates CAR T anti-tumor activity in various mouse tumor models. Collectively, this study unveils a mechanism for VISTA regulation in T cells and highlights targeting TRIM25–VISTA as a potential strategy to enhance tumor immunotherapy.</p>

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Destruction of VISTA by TRIM25 ablation in T cells potentiates cancer immunotherapy

  • 期刊论文

  • 发表日期：

    2025年11月13日

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  • Yishuang Sun,
  • Zijian Zhang,
  • Haiou Li,
  • Xia Bu,
  • Li Chen,
  • Xiyong Wang,
  • Lifang Fan,
  • Baoxiang Chen,
  • Lijun Kong,
  • Panpan Dai,
  • Wenjing Song,
  • Xiangling Xiao,
  • Jie Shi,
  • Bolin Xiang,
  • Chuan He,
  • Yingmeng Yao,
  • Wenjun Xiong,
  • Haisheng Yu,
  • Congqing Jiang,
  • Qun Qian,
  • Hudan Liu,
  • Sufang Tian,
  • Guoliang Qing,
  • Zhiyong Yang,
  • Wenyi Wei,
  • Gordon J. Freeman,
  • Haichuan Zhu,
  • Jinfang Zhang

摘要

The limited success of current immunotherapies emphasizes the need for new targets and combination treatments. V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target in cancer immunotherapy, but its regulatory mechanism is poorly understood. Through CRISPR knockout screening and proteomic analysis, we identify tripartite motif containing 25 (TRIM25) as a positive regulator for VISTA largely through antagonizing its degradation signaling. Moreover, ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, leading to VISTA stabilization. A VISTA-derived phospho-peptide competitively disrupts TRIM25–VISTA interaction, thereby reducing VISTA expression and potentiating the anti-tumor efficacy of PD-1/PD-L1 blockade. Moreover, single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in mice with T cell-specific knockout of Trim25. Of note, genetic ablation of Trim25 in T cells not only improves anti-PD-L1 immunotherapy, but also significantly ameliorates CAR T anti-tumor activity in various mouse tumor models. Collectively, this study unveils a mechanism for VISTA regulation in T cells and highlights targeting TRIM25–VISTA as a potential strategy to enhance tumor immunotherapy.