Platinum ^IV Complex Enabling Multiple and Potent Tumor Microenvironment Remodeling for Cancer Chemo-Immunotherapy

Tumor microenvironment not only compromises the therapeutic efficacy of chemotherapy but also weakens chemotherapy-induced immunogenic cell death. Herein, we report novel platinum^IV prodrugs that integrate two clinically approved drugs with different but complementary mechanisms, where cisplatin provides tumor cytotoxicity while the pirfenidone analogue contributes to tumor microenvironment modulation. In vitro evaluations suggested their superior anticancer activity, improved resistance profiles, and favorable selectivity across multiple cancer cell lines. Mechanistic studies revealed that they not only depleted intracellular glutathione and suppressed P-gp expression but also remodeled the tumor microenvironment through multiple actions. Notably, they triggered the release of damage-associated molecular patterns (DAMPs), promoted dendritic cell maturation, and induced strong immunogenic cell death despite that cisplatin is unable to induce an immunological response. In vivo studies further confirmed their antitumor activity (3.3-fold tumor inhibition compared to cisplatin) and favorable safety profile (64% weight loss by cisplatin, none with platinum^IV complexes).