Antitumor EF24 analogue-integrated platinum (IV) prodrugs induce autophagy-mediated immunogenic cell death and PD-L1 downregulation in colorectal cancer.

Abstract

The oxaliplatin-based therapy regimens for colorectal cancer (CRC) presents a significant challenge to clinical application owing to the severe side effects and drug resistance. To enhance the selectivity and therapeutic efficacy of oxaliplatin, we designed and synthesized a series of platinum (IV) prodrugs by conjugating NF-κB inhibitor EF24 analogs to an oxaliplatin -derived platinum (IV) complex. Among them, the platinum (IV) prodrug 6d demonstrated the most potent inhibitory effect on HCT-116/Oxa cells, 4T1 cells and CT26 cells in both in vitro and in vivo compared to oxaliplatin. Mechanistic studies indicated that 6d could induce significant DNA damage and suppress the MAPK/NF-κB signaling pathway, ultimately leading to CRC cell death. Especially, 6d induced cell death by promoting autophagy through suppressing the PI3K/AKT/mTOR signaling pathway, and suppressed the expression of PD-L1. More importantly, 6d triggered autophagy to mediate immunogenic cell death (ICD) effect both in vitro and in vivo, thereby eliciting antitumor immune responses. These findings indicate that 6d may represent a potential chemotherapeutic candidate for the treatment of CRC.