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

• Published in: Angewandte Chemie International Edition Vol. 61; no. 16; pp. e202115247 - n/a
• Main Authors: Wang, Wen‐Jin, Ling, Yu‐Yi, Zhong, Yan‐Mei, Li, Zhi‐Yuan, Tan, Cai‐Ping, Mao, Zong‐Wan
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 11.04.2022
• Edition: International ed. in English
• Subjects: Apoptosis; Cancer; Cancer immunotherapy; Cell death; Fenton-like reaction; Ferrocene; Ferroptosis; Free radicals; Gene sequencing; Glutathione; Glutathione peroxidase; Humans; Hydroxyl radicals; Immunity; Immunogenicity; Immunotherapy; Iridium; Iridium - pharmacology; Iridium(III) complex; Lipid Peroxidation; Lipids; Lymphocytes; Lymphocytes T; Lysosomes; Metallocenes; Microenvironments; Neoplasms - pathology; Peroxidase; Peroxidation; Sequence analysis; Tumor Microenvironment; Fenton-like reaction; Ferroptosis; Immunotherapy; Iridium(III) complex; Ferrocene
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202115247

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 IrIII 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. Ferroptosis‐inducing agents have potential as antitumor candidates. A ferrocene‐modified IrIII complex with Fenton‐like catalytic activity is used to disturb the cellular redox balance, which leads to lipid peroxidation and ferroptosis of cancer cells. Ferroptosis induced by the IrIII complex causes immunogenic cell death (ICD) of cancer cell in vitro, which enhances cancer immune response in vivo.