T细胞中TRIM25消融对VISTA的破坏增强了癌症免疫治疗，这一成果由武汉大学张金方小组经过不懈努力而取得。该项研究成果发表在2025年11月13日出版的《细胞研究》上。

通过CRISPR敲除筛选和蛋白质组学分析，研究小组确定tripartite motif containing 25 （TRIM25）主要通过拮抗其降解信号传导而成为VISTA的正调控因子。

此外，ERK介导的VISTA Thr284位点磷酸化增强了它与TRIM25的相互作用，导致VISTA稳定。VISTA衍生的磷酸化肽竞争性地破坏TRIM25-VISTA相互作用，从而降低VISTA表达并增强PD-1/PD-L1阻断的抗肿瘤功效。

此外，单细胞RNA测序分析显示，在T细胞特异性敲除Trim25的小鼠中，肿瘤浸润性细胞毒性CD8⁺ T细胞增加。值得注意的是，T细胞中Trim25的基因消融不仅改善了抗PD-L1免疫治疗，而且显著改善了各种无主题肿瘤模型中的CAR-T抗肿瘤活性。总的来说，这项研究揭示了VISTA在T细胞中的调节机制，并强调靶向TRIM25-VISTA是增强肿瘤免疫治疗的潜在策略。

研究人员表示，目前免疫疗法的有限成功强调需要新的靶点和联合治疗。V-domain Ig suppressor of T cell activation （VISTA）是肿瘤免疫治疗中一个很有前景的免疫检查点靶点，但其调控机制尚不清楚。

附：英文原文

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

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

Issue&Volume: 2025-11-13

Abstract: 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.

DOI: 10.1038/s41422-025-01186-5

Source: https://www.nature.com/articles/s41422-025-01186-5