Melanoma MHC-I-membrane-encapsulated Cu@ferrihydrite induces ferroptosis/cuproptosis and systematic immunity against tumor

Major histocompatibility complex I (MHC-I) has significant potential for augmenting cancer immunogenicity and immune recognition. Here, we report an innovative therapeutic strategy that synergistically integrates blue light-upregulated MHC-I expression with blue light-induced ferroptosis and cuproptosis. Blue light promoted MHC-I expression in mouse melanoma cells by modulating the NF-κB-SUSD6 signaling axis. Subsequently, an MHC-I-enriched melanoma cytomembrane was used to encapsulate the photoresponsive Cu@ferrihydrite (Cu@Fh) nanoparticles, forming M-Cu@Fh. MHC-I facilitated dendritic cells (DCs) maturation and CD8⁺/CD4⁺ T cells activation. M-Cu@Fh also triggered oxidative stress and concurrent ferroptosis/cuproptosis through the controllable release of Fe/Cu ions under blue-light irradiation. In vivo experiments demonstrated that the combination of blue light and M-Cu@Fh converted immune “cold” tumors into “hot” tumors, suppressed in situ melanoma growth through oxidative damages and enhanced immunogenicity. Furthermore, systemic activation of DCs and CD8⁺/CD4⁺ T cells in lymphoid organs (lymph nodes and spleen) and lungs conferred prophylactic efficacy against abscopal metastasis. Our study elucidates the photoregulatory mechanism of MHC-I in melanoma cells and presents a transformative combinatorial strategy that synergizes blue light-driven photoimmunotherapy (PIT) with blue light-activated photodynamic therapy (PDT) for melanoma management and metastasis prevention.