Optogenetic engineered macrophages for light-induced M1 polarization and enhanced chemo-immunotherapy in melanoma models

Macrophage-based adoptive cell therapies hold promise for solid tumors, but spatiotemporally controlling macrophage polarization within the immunosuppressive tumor microenvironment remains challenging. Here, we aimed to validate an optogenetic strategy using the LOV2-STIM1 system to achieve light-induced, sustained M1 polarization of macrophages. Upon blue light stimulation, engineered macrophages robustly exhibited M1 phenotypes, suppressed melanoma cell proliferation, migration, and invasion in vitro, and recapitulated the antitumor functions of M1 macrophages. Notably, combining light-activated engineered macrophages with temozolomide in melanoma models resulted in synergistic inhibition of tumor growth. This synergy is accompanied by a profound remodeling of the tumor immune microenvironment, characterized by M1-driven reversal of chemoresistance and enhanced infiltration of cytotoxic CD8⁺ T cells. Our findings establish a proof-of-concept for optogenetic regulation of macrophage polarization and demonstrate its feasibility for enhancing antitumor effects and chemosensitivity in melanoma models, providing a promising and controllable platform for macrophage-based immunotherapy.