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: 987-1002

ORIGINAL ARTICLES

Targeted destruction of VISTA boosts anti-tumor immunotherapy

Li Chen^1,† , Xia Bu^2,† , Yishuang Sun^3,† , Daoyuan Huang^1,† , Yong Chen^4,† , Tao Hou^1,† , Xiaoping Hu⁵ , Jingchao Wang¹ , Peiqiang Yan¹ , Yihang Qi¹ , Weiwei Jiang¹ , Yan Xiong⁵ , Jing Liu⁶ , Yang Gao⁶ , Mengxi Huan⁶ , Bin Wang⁷ , Qianjia Liu⁸ , Xiaoming Dai⁹ , Fabin Dang¹⁰ , John M. Asara¹¹ , Masanori Fujimoto⁴ , Hiroyuki Inuzuka¹ , Jian Jin⁵ , Jinfang Zhang^12,13,* , Gordon J. Freeman^2,* , Wenyi Wei^1,*

¹Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
²Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
³Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
⁴Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
⁵Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
⁶Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
⁷Department of Breast Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
⁸College of Life Sciences, Wuhan University, Wuhan, Hubei, China
⁹Institute of Modern Biology, Nanjing University, Nanjing, Jiangsu, China
¹⁰Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
¹¹Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA
¹²Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
¹³State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China
^†These authors contributed equally: Li Chen, Xia Bu, Yishuang Sun, Daoyuan Huang, Yong Chen, Tao Hou
Correspondence: Jinfang Zhang(jinfang_zhang@whu.edu.cn)Gordon J. Freeman(gordon_freeman@dfci.harvard.edu)Wenyi Wei(wwei2@bidmc.harvard.edu)

Immune checkpoints serve as regulatory pathways that are essential for regulating immune response and homeostasis. As such, many components along the pathway have emerged as pivotal targets in cancer therapy. To overcome the treatment resistance and limited efficacy encountered by current immune checkpoint therapies, there is an urgent need for new immunotherapeutic targets and strategies. V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint protein with a unique expression pattern and has emerged as a novel therapeutic target in anti-tumor immunotherapy; however, the precise role of VISTA and its regulatory mechanisms in tumor cells remain incompletely understood. Here, we identify a novel strategy targeting VISTA for cancer immunotherapy, enhancing therapeutic outcomes. Mechanistically, we show that VISTA undergoes anaphase-promoting complex/cyclosome (APC/C)/CDH1-mediated ubiquitination and subsequent proteasomal degradation, a process that can be reversed by the deubiquitinase USP2. Therapeutically, the USP2 inhibitor MS102 significantly reduces VISTA protein abundance in vitro and in vivo, enhances T cell responses, and synergizes with anti-PD-1 immunotherapy to improve survival in syngeneic mouse tumor models. Our findings reveal a regulatory network for VISTA stability control and support the combination of USP2 inhibitors with anti-PD-1 immunotherapy to enhance anti-tumor immune responses.

https://doi.org/10.1038/s41422-025-01194-5

FULL TEXT | PDF

Browse 83