The unique microenvironment of solid tumors, characterized by pathological hypoxia, remains a primary driver of treatment resistance and poor clinical outcomes in oncology. While photodynamic therapy has emerged as a promising treatment modality, its clinical efficacy is constrained by its dependence on molecular oxygen. Conventional photosensitizers typically operate by oxygen-dependent energy transfer, leading to a marked reduction or complete loss of therapeutic activity within the oxygen-depleted regions of solid tumors. Herein, we show that iron coordination can serve as a molecular switch to enable the photochemical reactivity of a ruthenium(II) polypyridine complex to an oxygen-independent pathway. Under normoxic conditions, the conjugate undergoes energy transfer to produce singlet oxygen. However, upon binding intracellular iron, the system activates an alternative mechanism characterized by ultrafast metal-to-metal electron transfer from the ruthenium(II) center to the iron center. This process enables the formation of cytotoxic hydroxyl radicals from endogenous hydrogen peroxide, ensuring potent phototoxicity even under severe hypoxia. We demonstrate that the resulting mitochondrial oxidative stress induces significant lipid peroxidation and glutathione depletion, ultimately triggering cell death by ferroptosis in both nonresistant and multidrug-resistant cancer cell lines. These findings establish metal-to-metal electron transfer as a general design logic for directing excited-state pathways and provide a conceptual basis for adaptive, hypoxia-tolerant photochemical systems.
Montesdeoca et al. (2026) studied this question.