NADH-Triggered Photogenerated Carbon Radicals as General Abstracting Agents for Synergism of Apoptosis and Ferroptosis

Free radicals, with their high reactivity, offer a promising strategy for tumor treatment by effectively circumventing drug resistance. Free-radical-based cancer therapies include radiotherapy, chemotherapy, and emerging approaches such as chemodynamic therapy (CDT) and photodynamic therapy (PDT). Conventional PDT, widely used in cancer treatment, relies on excited photosensitizers generating reactive oxygen species (ROS) via electron or energy transfer to kill cancer cells. However, the generation of both Type I and Type II ROS critically depends on microoxic and normoxic conditions, and the hypoxic tumor microenvironment severely limits therapeutic efficacy. Enhancing the cancer-cell-killing effect of PDT remains challenging. Herein, we constructed an S-rhodamine photosensitizer activated upon photoirradiation and NADH induction, generating a sulfur-bridged xanthene-based triarylmethyl radical (TAM^•) in an oxygen-independent manner. Acting as a broad-spectrum hydrogen atom abstractor, this radical attacks biomolecules within cancer cells more effectively than ROS by extracting hydrogen atoms from endogenous biological substrates, depleting intracellular NADH and glutathione (GSH), and causing critical DNA damage. These actions induce severe DNA damage and disrupt intracellular homeostasis, ultimately eradicating cancer cells through a combination of ferroptosis and apoptosis. It exhibited potent antitumor activity in the 4T-1 tumor-bearing mouse model. This design strategy for modulating the stability of photogenerated carbon radicals holds significant promise for the development of novel anticancer agents.