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, CJ2 had the most potent therapeutic
activity and less toxicity. With the introduction of ligand JQ-1, CJ2-reduced PD-L1 protein was found
in the cytoplasm and cytomembrane for the first time. By interfering
with the PD-L1 synthesis, CJ2 could arouse the immune system and promote CD8+ T cell
infiltration. Meanwhile, CJ2 could
accelerate PD-L1 degradation in the cytoplasm to block DNA damage
repair. In vivo, CJ2 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.