<b>CJ</b><sub><b>2</b></sub>: A Novel Potent Platinum(IV) Prodrug Enhances Chemo-Immunotherapy by Facilitating PD-L1 Degradation in the Cytoplasm and Cytomembrane
Renming Fan, Aohua Deng, Bing Qi, Shuo Zhang, Ruoxi Sang, Lanxin Luo, Jiakui Gou, Yongqing Liu, Yongqing Liu, Ruizhuo Lin, Ming Zhao, Yang Liu, Yang Liu, Le Yang, Maosheng Cheng, Gaofei Wei
Abstract
Platinum drugs as primary chemotherapy drugs have been applied to various cancer patients. However, their therapeutic applicability is limited due to the adverse effects and immunosuppression. To minimize the side effects and boost the immune response, we designed and synthesized platinum(IV) prodrugs that introduced BRD4 inhibitor JQ-1. Among them, CJ 2 had the most potent therapeutic activity and less toxicity. With the introduction of ligand JQ-1, CJ 2 -reduced PD-L1 protein was found in the cytoplasm and cytomembrane for the first time. By interfering with the PD-L1 synthesis, CJ 2 could arouse the immune system and promote CD8 + T cell infiltration. Meanwhile, CJ 2 could accelerate PD-L1 degradation in the cytoplasm to block DNA damage repair. In vivo, CJ 2 markedly suppressed tumor growth by reversing the immunosuppression microenvironment and enhancing DNA damage. These findings provide an effective approach to improve the selectivity and activity of the platinum drugs with elevated immune response.