Manganese-Enriched Zinc Peroxide Functional Nanoparticles for Potentiating Cancer Immunotherapy

Immunotherapies have shown high clinical success, however, the therapeutical efficacy is largely restrained by insufficient immune activation and an immunosuppressive microenvironment. Herein, we report tumor microenvironment (TME)-responsive manganese-enriched zinc peroxide nanoparticles (MONPs) for synergistic cancer immunotherapy by inducing the immunogenic death (ICD) of cancer cells and activating the stimulator of the interferon gene (STING) pathway. MONPs especially disassociate upon exposure to acidic tumor tissue and in situ generate •OH for the ICD effect. Moreover, Mn²⁺ activated the STING and synergistically induced the secretion of type I interferon and inflammatory cytokines for specific T cell responses. Meanwhile, MONPs relieved the immunosuppression of TME through decreasing Tregs and polarizing M2 macrophages to the M1 type to unleash a cascade adaptive immune response. In combination with the anti-PD-1 antibody, MONPs showed superior efficacy in inhibiting tumor growth and preventing lung metastasis. Our study demonstrates the feasibility of functional nanoparticles to amplify STING innate stimulation, showing a prominent strategy for cancer immunotherapy.