2. Academic Validation
  3. Targeted destruction of VISTA boosts anti-tumor immunotherapy

Targeted destruction of VISTA boosts anti-tumor immunotherapy

  • Cell Res. 2025 Dec;35(12):987-1002. doi: 10.1038/s41422-025-01194-5.
Li Chen # 1,  Xia Bu # 2,  Yishuang Sun # 3,  Daoyuan Huang # 1,  Yong Chen # 4,  Tao Hou # 1,  Xiaoping Hu 5,  Jingchao Wang 1,  Peiqiang Yan 1,  Yihang Qi 1,  Weiwei Jiang 1,  Yan Xiong 5,  Jing Liu 6,  Yang Gao 6,  Mengxi Huan 6,  Bin Wang 7,  Qianjia Liu 8,  Xiaoming Dai 9,  Fabin Dang 10,  John M Asara 11,  Masanori Fujimoto 4,  Hiroyuki Inuzuka 1,  Jian Jin 5,  Jinfang Zhang 12 13,  Gordon J Freeman 14,  Wenyi Wei 15
Affiliations

Affiliations

  • 1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China.
  • 4 Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 5 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 6 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 7 Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 8 College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
  • 9 Institute of Modern Biology, Nanjing University, Nanjing, Jiangsu, China.
  • 10 Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
  • 11 Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 12 Department 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. [email protected].
  • 13 State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China. [email protected].
  • 14 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
  • 15 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 41225154 DOI: 10.1038/s41422-025-01194-5
Abstract

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.

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