Ferroptosis-Enhanced Cancer Immunity by a Ferrocene-Appended Iridium(III) Diphosphine Complex

Ferroptosis is a programmed cell death pathway discovered in recent years, and ferroptosis-inducing agents have great potential as new antitumor candidates. Here, we report a Ir^III complex (Ir1) containing a ferrocene-modified diphosphine ligand that localizes in lysosomes. Under the acidic environments of lysosomes, Ir1 can effectively catalyze Fenton-like reaction, produce hydroxyl radicals, induce lipid peroxidation, down-regulate glutathione peroxidase 4, and result in ferroptosis. RNA sequencing analysis shows that Ir1 can significantly affect pathways related to ferroptosis and cancer immunity. Accordingly, Ir1 can induce immunogenic cells death and suppress tumor growth in vitro, regulate T cell activity and immune microenvironments in vivo. In conclusion, we show the potential of small molecules with ferroptosis-inducing capabilities for effective cancer immunotherapy.