A Catalytic Osmium Redox Couple Collapses Cancer Redox Balance

Developing agents that disrupt the redox balance of tumor cells by simultaneously increasing reactive oxygen species (ROS) and decreasing antioxidants offers a promising approach in chemotherapy. Here, we present an isolable, interconvertible osmium redox pair, trans-[Os^III(NHPPh₃)(L)(4-Me₂Npy)]⁺ and trans-[Os^IV(NHPPh₃)(L)(4-Me₂Npy)]^{2 +} [Os(III) and Os(IV)]. This self-sustaining redox cycle of Os(III) and Os(IV) exhibit dual-mode catalytic activity, experimental results show that Os(III) catalyses Fenton-like activation of H₂O₂ to produce hydroxyl radicals, whereas Os(IV) oxidizes GSH to GSSG, regenerating Os(III) within cells. This cycle disrupts cellular redox homeostasis, prompting apoptosis and ferroptosis, and displays features of immunogenic cell death. In vivo, both Os(III) and Os(IV) inhibit tumor growth with good tolerability and enhance antitumor immune responses. These findings position redox-cycling metal complexes as a promising strategy to target cancer redox vulnerabilities, encouraging further exploration of combination therapies with immunotherapeutic agents.