Manganese-Activatable Nano-Hydroxyapatite Nanoparticles as Self-Adjuvanting STING Activators for Synergistic Melanoma Therapy

Abstract

The immunosuppressive tumor microenvironment in malignant melanoma presents a major therapeutic challenge, often leading to treatment failure of conventional monotherapies. This critical limitation underscores the urgent need for innovative biocompatible and robust adjuvants capable of locally reactivating anti-tumor immunity while overcoming tumor heterogeneity and minimizing systemic toxicity. Here we develop a manganese-activatable nano-hydroxyapatite platform (nHA-Mn) that functions as a self-adjuvanting STING activator for synergistic melanoma therapy. By employing a surface complexation strategy that preserves nHA's inherent crystalline structure and biocompatibility, we successfully constructed a nanoplatform with pH-responsive ions release characteristics, enabling targeted delivery of both Ca2+ and Mn2+ specifically within acidic tumor microenvironment. This sophisticated design achieves simultaneous induction of mitochondrial dysfunction-mediated apoptosis through Ca2+ overload and potentiation of robust anti-tumor immunity via STING pathway activation. The coordinated immunomodulatory response significantly enhances tumor immunogenicity through MHC molecules upregulation, promotes dendritic cell maturation, and facilitates substantial infiltration of CD4+/CD8+ T cells accompanied by elevated IFN-γ production. Importantly, nHA-Mn demonstrates potent tumor growth suppression and induces protective immune memory formation while maintaining excellent biosafety profiles in vivo. Hence, this study establishes a broadly applicable therapeutic platform that uniquely integrates direct tumor cytotoxicity with self-adjuvanting immune activation, highlighting the promising potential of rational metal ions engineering in advancing next-generation cancer immunotherapy.