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 mi-croenvironment (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 phago-cytized with TAMs. The UIONPs moiety efficiently relieved the ITM by repolarizing TAMs into M1-pheno-type, while PHMA activated the STING pathway and stimulated type-I interferon (e.g., IFN-beta) secretion in TAMs. Consequently, IFN-beta 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 na-nocomplexes-mediated TAM repolarization and subsequent STING activation, which might provide novel insights for potentiating cancer immunotherapy. (c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

This study developed bioinspired magnetic nanocomplexes to enhance antitumor immunogenicity by amplifying the STING-regulated immune cascade of TAMs. The nanocomplexes specifically accumulated at the tumor site and repolarized TAMs into antitumor M1 phenotype, leading to activation of the STING pathway and priming of tumor-specific CTLs. In combination with immune checkpoint blockade therapy, the nanocomplexes effectively inhibited tumor growth and prolonged survival in mouse models, providing new insights for cancer immunotherapy.