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

Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation (LPO) with potential of antitumor immunity activation. Herein, a nonferrous cyclopentadienyl metal-based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl (Ir-Bet) is developed via metal-ligand synergistic enhancement (MLSE) strategy by the reaction of [Ir(Cp*)Cl]2 with natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir-Cp*) species as Ir-Bet not only tremendously enhances the antiproliferative activity toward cancer cells, but also activates ferritinophagy for iron homeostasis regulation by PI3k/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evokes immune response by nuclear factor kappa-B (NF-κB) activation of Ir-Cp* species. Further immunogenic cell death (ICD) is intensified by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. The in vivo vaccination experiment demonstrates desirable antitumor and immunogenic effects of Ir-Bet by increasing ratio of cytotoxic T cells (CTLs) / regulatory T cells (Tregs). This work provides a new approach for future development of effective metal-based immunochemotherapeutic agents via MLSE strategy from metal species and natural products.