Ethanol-induced cellular metastable state sensitization for copper-based oxidative tumor therapy

Ethanol-induced intracellular reactive oxygen species storm offers inspiration for oxidative tumor therapy. Although ethanol-based treatments provide benefits such as affordability and low toxicity, their safety and therapeutic efficiency still face challenges. Herein, we develop a polyethylene glycol-stabilized nano-sized copper ethoxide (Nano-CuEOP), enabling safe and efficient ethanol delivery. Upon endocytosis by melanoma cells, Nano-CuEOP releases ethanol and transforms into nano-copper oxide aggregates (Nano-HCuEO). The ethanol-induced "sub-toxic" effect upregulates the expression of intracellular cytochrome P450 2E1, driving the cells into a metastable state with heightened susceptibility to transition metals. This, in turn, enhances the catalytic activity and copper ion toxicity of Nano-HCuEO. A single intratumoral Nano-CuEOP injection achieves efficient melanoma treatment and remolds the immune microenvironment. Combined with αPD-1, the system triggers a strong systemic anti-tumor response. This study introduces an ethanol-induced metastable state modulation strategy to sensitize copper-based tumor therapy and advances the application of metal alkoxides in cancer treatment.