靶向破坏VISTA促进抗肿瘤免疫治疗，这一成果由美国哈佛大学医学院魏文毅研究小组经过不懈努力而取得。相关论文于2025年11月13日发表在《细胞研究》杂志上。

该课题组人员确定了一种针对VISTA的癌症免疫治疗新策略，提高了治疗效果。在机制上，课题组研究人员发现VISTA经历了后期促进复合物/环体(APC/C)/ CDH1介导的泛素化和随后的蛋白酶体降解，这一过程可以通过去泛素酶USP2逆转。在治疗上，USP2抑制剂MS102在体外和体内显著降低VISTA蛋白丰度，增强T细胞反应，并与抗PD-1免疫疗法协同作用，提高同基因单主题肿瘤模型的生存率。他们的发现揭示了VISTA稳定性控制的调控网络，并支持USP2抑制剂与抗PD-1免疫疗法的联合使用，以增强抗肿瘤免疫反应。

据悉，免疫检查点是调节免疫反应和体内平衡的重要途径。因此，该通路上的许多成分已成为癌症治疗的关键靶点。为了克服目前免疫检查点疗法所遇到的治疗耐药性和有限的疗效，迫切需要新的免疫治疗靶点和策略。V-domain Ig suppressor of T cell activation （VISTA）是一种具有独特表达模式的免疫检查点蛋白，已成为抗肿瘤免疫治疗的新靶点；然而，VISTA在肿瘤细胞中的确切作用及其调控机制尚不完全清楚。

附：英文原文

Title: Targeted destruction of VISTA boosts anti-tumor immunotherapy

Author: Chen, Li, Bu, Xia, Sun, Yishuang, Huang, Daoyuan, Chen, Yong, Hou, Tao, Hu, Xiaoping, Wang, Jingchao, Yan, Peiqiang, Qi, Yihang, Jiang, Weiwei, Xiong, Yan, Liu, Jing, Gao, Yang, Huan, Mengxi, Wang, Bin, Liu, Qianjia, Dai, Xiaoming, Dang, Fabin, Asara, John M., Fujimoto, Masanori, Inuzuka, Hiroyuki, Jin, Jian, Zhang, Jinfang, Freeman, Gordon J., Wei, Wenyi

Issue&Volume: 2025-11-13

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.

DOI: 10.1038/s41422-025-01194-5

Source: https://www.nature.com/articles/s41422-025-01194-5