Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Mol Ther. 2021 Mar 3;29(3):908-919. doi: 10.1016/j.ymthe.2020.12.032. Epub 2021 Jan 1.
A growing amount of evidence suggests that ubiquitination and deubiquitination of programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) play crucial roles in the regulation of PD-1 and PD-L1 protein stabilization and dynamics. PD-1/PD-L1 is a major coinhibitory checkpoint pathway that modulates immune escape in cancer patients, and its engagement and inhibition has significantly reshaped the landscape of tumor clearance. The abnormal ubiquitination and deubiquitination of PD-1/PD-L1 influence PD-1/PD-L1-mediated immunosuppression. In this review, we describe the ubiquitination- and deubiquitination-mediated modulation of PD-1/PD-L1 signaling through a variety of E3 ligases and deubiquitinating enzymes (DUBs). Moreover, we briefly expound on the anticancer potential of some agents that target related E3 ligases, which further modulate the ubiquitination of PD-1/PD-L1 in cancers. Therefore, this review reveals the development of a highly promising therapeutic approach for cancer immunotherapy by targeting PD-1/PD-L1 ubiquitination.
越来越多的证据表明，程序性死亡受体 1（PD-1）/程序性死亡配体 1（PD-L1）的泛素化和去泛素化在 PD-1 和 PD-L1 蛋白稳定和动态调节中起着关键作用。PD-1/PD-L1 是一个主要的共抑制检查点通路，调节癌症患者的免疫逃逸，其结合和抑制显著改变了肿瘤清除的格局。PD-1/PD-L1 的异常泛素化和去泛素化影响 PD-1/PD-L1 介导的免疫抑制。在这篇综述中，我们描述了通过各种 E3 连接酶和去泛素化酶（DUBs）对 PD-1/PD-L1 信号的泛素化和去泛素化调节。此外，我们还简要阐述了一些针对相关 E3 连接酶的抗癌药物的潜力，这些药物进一步调节了癌症中 PD-1/PD-L1 的泛素化。因此，通过靶向 PD-1/PD-L1 泛素化，本综述揭示了一种针对癌症免疫治疗的极具前景的治疗方法的发展。
