Oxime Sulfonates‐Based Photoinitiator Activates Pyroptosis and Ferroptosis for Hypoxia Tumor Therapy

ABSTRACT The development of biocompatible and efficient photo‐triggered hydrogen abstraction systems holds considerable promise for the oxidation of NADH, thereby disrupting the NADH/NAD+ balance, modulating redox homeostasis, and advancing therapeutic approaches for hypoxic tumors. In this study, an oxime sulfonate‐based hydrogen abstraction photoinitiator (TSA) is designed to induce pyroptosis and ferroptosis for tumor therapy. TSA generates type‐I ROS (O 2 •− and •OH) based on the type‐I photodynamic mechanism. Moreover, TSA undergoes photolysis to yield aryl and sulfonyl free radicals, which exhibit H‐abstraction activity toward intracellular biomolecules, resulting in NADH oxidation and the reduction of cytochrome c (cyt c, Fe 3+ ). Concurrently, TSA preferentially accumulates within mitochondria, depletes glutathione (GSH), elevates lipid peroxide levels, and downregulates glutathione peroxidase 4, culminating in mitochondrial dysfunction and ferroptosis. Additionally, photoinduced pyroptotic cell death was observed through activation of the caspase‐1/gasdermin D signaling pathway. TSA also induces immunogenic cell death, promotes dendritic cell maturation and migration, and facilitates the recruitment of cytotoxic T lymphocytes, thereby enhancing adaptive immune responses critical for effective cancer immunotherapy. Collectively, these findings highlight the potential of employing an oxime sulfonate‐based photoinitiator to manipulate intracellular photo‐triggered hydrogen abstraction reactions, offering a promising strategy for activating ferroptosis and pyroptosis in the treatment of hypoxic tumors.