Since Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as an important pathway for p53 regulation. Like Mdm2, VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis also regulates PD-L1 (programmed death-ligand 1) expression. Strikingly, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2, knockout of Usp2 in mice has no obvious effect in normal tissues. Moreover, no obvious toxicity is observed upon the USP2 inhibitor treatment in vivo as Mdm2-mediated regulation of p53 remains intact. Our study reveals a promising strategy for p53-based therapy by circumventing the toxicity issue.

由于 Mdm2（小鼠双分钟 2）抑制剂在临床研究中显示出严重的毒性，因此需要探索不同的方法来实现癌症中 p53 介导的肿瘤抑制的治疗再激活。在这里，我们将 USP2（泛素特异性肽酶 2）-VPRBP（病毒蛋白 R 结合蛋白）轴确定为 p53 调节的重要途径。与 Mdm2 一样，VPRBP 是 p53 的有效抑制因子，但 VPRBP 稳定性由 USP2 控制。有趣的是，USP2-VPRBP 轴还调节 PD-L1（程序性死亡配体 1）的表达。引人注目的是，小分子 USP2 抑制剂和抗 PD1 单克隆抗体的组合导致表达野生型 p53 的肿瘤完全消退。与Mdm2相比，小鼠中Usp2的敲除对正常组织没有明显影响。此外，在体内USP2抑制剂治疗后没有观察到明显的毒性，因为Mdm2介导的p53调节保持完整。我们的研究通过规避毒性问题揭示了基于 p53 的治疗的一种有前途的策略。