Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium‐Betulin Immune Agonist

Abstract Ferroptosis is a form of programmed cell death driven by iron‐dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal‐based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl ( Ir‐Bet ) was developed by a metal‐ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl] 2 Cl 2 with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir‐Cp*) species as Ir‐Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa‐B (NF‐κB) activation of Ir‐Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir‐Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs).