Photoinduced Cuproptosis with Tumor-Specific for Metastasis-Inhibited Cancer Therapy

Cuproptosis is a novel form of regulated cell death which guarantees to increase the efficacy of existing anticancer treatments that employ traditional apoptotic therapeutics. However, reducing the amount of undesirable Cu ions released in normal tissue and maximizing Cu-induced cuproptosis therapeutic effects at tumor sites are the major challenges. In this study, exploiting the chemical properties of copper ionophores and the tumor microenvironment, a novel method is developed for controlling the valence of copper ions that cause photoinduced cuproptosis in tumor cells. CJS-Cu nanoparticles (NPs) can selectively induce cuproptosis after cascade reactions through H2O2-triggered Cu2+ release, photoirradiation-induced superoxide radical (center dot O2-) generation, and reduction of Cu2+ to Cu+ by center dot O2-. The generated reactive oxygen species can result in glutathione depletion and iron-sulfur cluster protein damage and further augmented cuproptosis. CJS-Cu NPs effectively suppressed tumor growth and downregulated the expression of metastasis-related proteins, contributing to the complete inhibition of lung metastasis. Ultimately, this study suggests novel avenues for the manipulation of cellular cuproptosis through photochemical reactions. A novel photoreactor, which is composed by Cu+-selective chelator and mitochondria-localized type-I photosensitizer can selectively induce cuproptosis after cascade reactions through H2O2-triggered Cu2+ release, photoirradiation-induced superoxide radical (center dot O2-) generation, and reduction of Cu2+ to Cu+ by center dot O2-. Furthermore, elevated reactive oxygen species production accelerates the loss of iron-sulfur cluster proteins and the depletion of GSH, which further augment cuproptos.image