Bioinspired magnetic nanocomplexes amplifying STING activation of tumor-associated macrophages to potentiate cancer immunotherapy

Insufficient tumor-infiltration of the cytotoxic T lymphocytes (CTLs) and immunosuppressive tumor microenvironment (ITM) severely hinder T cell-based cancer immunotherapy. In this study, we developed bioinspired magnetic nanocomplexes (m-PUNCs) to boost antitumor immunogenicity through amplifying stimulator of interferon genes (STING)-regulated immune cascade of tumor-associated macrophages (TAMs). m-PUNCs were engineered by integrating ultrasmall iron oxide nanoparticles (UIONPs), tumor acidity-ionizable of poly(ethylene glycol)-block-poly(2-(hexamethyleneimino)) ethyl methacrylate (PHMA) diblock copolymer, and red blood cell membrane into a single nanoplatform. The resultant m-PUNCs specifically accumulated at the tumor site via passive targeting effect, which were subsequently phagocytized with TAMs. The UIONPs moiety efficiently relieved the ITM by repolarizing TAMs into M1-phenotype, while PHMA activated the STING pathway and stimulated type-I interferon (e.g., IFN-β) secretion in TAMs. Consequently, IFN-β attracted the conventional type I dendritic cells for priming the tumor-specific CTLs. In combination with immune checkpoint blockade therapy with the antibody against programmed death ligand 1, m-PUNCs remarkably inhibited tumor growth and prolonged the survival of both melanoma and breast tumor-bearing mouse model. This study demonstrated the immune cascade of magnetic nanocomplexes-mediated TAM repolarization and subsequent STING activation, which might provide novel insights for potentiating cancer immunotherapy.