Dual-Targeting Cuproptosis and Mitophagy via a Flavopiridol-Copper Nanoplatform Potentiates Immunotherapy Against Uveal Melanoma.

Uveal melanoma (UM) is a highly therapy-resistant ocular malignancy with an immunosuppressive tumor microenvironment (TME) and low tumor mutational burden. Here, we developed NP@Fla-Cu, a glutathione (GSH)-responsive nanoparticle designed to co-induce cuproptosis and mitophagy dysregulation. Cuproptosis, a copper-dependent mitochondrial cell death pathway, is amplified by NP@Fla-Cu's dual functionality: its GSH-degradable shell depletes copper-chelating GSH, while its core delivers a flavopiridol-copper complex (Fla-Cu). Flavopiridol acts as a copper ionophore, driving mitochondrial copper overload to trigger cuproptosis, while hyperactivating mitophagy, causing organelle depletion and metabolic collapse. In UM intraocular orthotopic xenograft models, NP@Fla-Cu exhibited tumor-specific accumulation and potent antitumor activity. Immunological evaluation in a B16F10 murine melanoma model further demonstrated that NP@Fla-Cu effectively remodeled the tumor immune microenvironment, as evidenced by enhanced CD8+ T cell infiltration. By synergizing copper cytotoxicity with immunomodulation, this nanoplatform sensitizes immune-cold UM to immunotherapy. This work establishes cuproptosis induction via NP@Fla-Cu as a transformative strategy against UM, effectively addressing challenges in tumor selectivity and off-target toxicity. The dual functionality of flavopiridol as a copper ionophore and mitophagy activator provides a promising combinatorial approach to overcome therapy resistance in immunosuppressive malignancies.