Volume 35, No 12, Dec 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 12, December 2025: 1003-1020

ORIGINAL ARTICLES

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

Yishuang Sun^1,2,3,† , Zijian Zhang^4,5,† , Haiou Li^6,† , Xia Bu^7,† , Li Chen^8,† , Xiyong Wang^1,3 , Lifang Fan² , Baoxiang Chen⁹ , Lijun Kong^1,3 , Panpan Dai¹⁰ , Wenjing Song¹ , Xiangling Xiao^1,3 , Jie Shi^1,3 , Bolin Xiang^1,3 , Chuan He^1,3 , Yingmeng Yao^1,3 , Wenjun Xiong^1,3 , Haisheng Yu^1,3 , Congqing Jiang⁹ , Qun Qian⁹ , Hudan Liu^1,3 , Sufang Tian² , Guoliang Qing^1,3 , Zhiyong Yang¹ , Wenyi Wei^8,* , Gordon J. Freeman^7,* , Haichuan Zhu^5,* , Jinfang Zhang^1,3,10

¹Department of Hepatobiliary and Pancreatic Surgery, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
²Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
³Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China
⁴Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, China
⁵National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei, China
⁶Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
⁷Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
⁸Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
⁹Department of Colorectal and Anal Surgery, Low Rectal Cancer Diagnosis and Treatment Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
¹⁰Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
^†These authors contributed equally: Yishuang Sun, Zijian Zhang, Haiou Li, Xia Bu, Li Chen
Correspondence: Wenyi Wei(wwei2@bidmc.harvard.edu)Gordon J. Freeman(gordon_freeman@dfci.harvard.edu)Haichuan Zhu(zhuhaichuan@163.com)

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.

https://doi.org/10.1038/s41422-025-01186-5

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