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

ABSTRACT 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.