ROS‐Responsive Doxorubicin Prodrug‐Manganese Nanoplatform Synergistically Activates cGAS‐STING to Suppress Uveal Melanoma Growth and Metastasis

ABSTRACT Tumor‐derived DNA released during chemo‐ or radiotherapy serves as a damage‐associated molecular pattern that activates antitumor immunity through the cGAS‐STING pathway. However, conventional chemotherapy is limited by insufficient tumoricidal efficacy and systemic toxicity, restricting effective activation of innate immune within a tolerable therapeutic window. Here, we report a ROS–responsive nanomedicine (NPDM) for coordinated chemotherapy and cGAS–STING activation. NPDM is constructed via the co‐self‐assembly of a lipidic doxorubicin (DOX) prodrug (C16‐SS‐DOX) and a manganese–polyphenol coordination polymer (HSSD‐Mn). NPDM exhibits high stability during systemic circulation while selectively releasing DOX and Mn 2 + within the ROS‐rich tumor microenvironment. Released DOX induces tumor DNA damage and DAMPs generation, whereas Mn 2 + acts as an endogenous cofactor to amplify cGAS–STING activation, thereby enhancing antigen‐presenting cell function and downstream antitumor immune responses. As a result, NPDM effectively suppresses tumor growth and elicits potent systemic immune activation. Notably, NPDM significantly sensitizes tumors to immune checkpoint blockade, and its combination with αPD‐L1 produces strong synergistic inhibition of both orthotopic and abscopal tumors. Collectively, this work constructs a novel nanoplatform integrating dual functions of “precise chemotherapeutic delivery” and “targeted activation of the cGAS‐STING pathway”, providing a promising chemo‐immunotherapy strategy for uveal melanoma and other immunologically “cold” tumors.