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 ion-release characteristics, enabling targeted delivery of both Ca²⁺ and Mn²⁺ specifically within acidic tumor microenvironments. This sophisticated design enables Mn²⁺ to synergistically enhance the induction of mitochondrial dysfunction-mediated apoptosis through nHA and the potentiation of robust anti-tumor immunity via an ICD response. Furthermore, nHA–Mn can enhance anti-tumor immunity through activation of the STING pathway. The coordinated immunomodulatory response significantly enhances tumor immunogenicity through MHC molecule upregulation, promotes dendritic cell maturation, and facilitates substantial infiltration of CD4⁺ T cells and CD8⁺ T cells accompanied by elevated IFN-γ production. Importantly, nHA–Mn demonstrates potent tumor growth suppression and induces immune memory T cell 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 ion engineering in advancing next-generation cancer immunotherapy.