Disruption of Zinc Homeostasis by a Novel Platinum(IV)‐Terthiophene Complex for Antitumor Immunity

Abstract Zinc homeostatic medicine is of great potential for cancer chemo‐immunotherapy; however, there are few reports on antitumor compounds that can trigger Zn 2+ ‐mediated immune responses. In this work, we developed a novel cyclometalated Pt IV ‐terthiophene complex, Pt3 , that not only induces DNA damage and cellular metabolism dysregulation, but also disrupts zinc homeostasis as indicated by the abnormal transcriptional level of zinc regulatory proteins, excess accumulation of Zn 2+ in cytoplasm, and down‐regulation of metallothioneins (MTs), which further caused redox imbalance. The simultaneous disruption of zinc and redox homeostasis in response to Pt3 treatment activated gasdermin‐D mediated pyroptosis accompanied by cytoskeleton remodeling, thus releasing pro‐inflammatory cytokines to promote dendritic cell (DC) maturation and T cell tumor‐infiltration, eventually eliminating both primary and distant tumors in vivo. As far as we know, this is the first metal complex that can regulate zinc homeostasis to activate antitumor immunity.