Metal‐Cyclic Dinucleotide Nanomodulator‐Stimulated STING Signaling for Strengthened Radioimmunotherapy of Large Tumor

Abstract Combined treatment of immunotherapy and radiotherapy shows promising therapeutic effects for the regression of a variety of cancers. However, even multi‐modality therapies often fail to antagonize the regression of large tumors due to the extremely immunosuppressive tumor microenvironment (TME). Here, a radioimmunotherapeutic paradigm based on stimulator of interferon genes (STING)‐dependent signaling is applied to preclude large tumor progression by utilizing the metal‐cyclic dinucleotide (CDN) nanoplatform, which integrates STING agonist c‐di‐AMP and immunomodulating microelement manganese (II) within the tannic acid nanostructure (TMA‐NPs). As observed by magnetic resonance imaging, the localized administration of TMA‐NPs effectively relieves hypoxia within TME and causes radical oxygen species overproduction and apoptosis in cancer cells after exposure to X‐ray irradiation. The DNA fragments released from the apoptotic cells after the combined treatment augment the production of endogenous CDNs in cancer cells, hence significantly activating the STING‐mediated pathway for stronger anti‐tumor immunity. The localized therapy of TMA‐NPs + X‐ray not only inhibits the primary large tumor progression but also retards distant tumor growth by promoting dendritic cell maturation and activating cytotoxic immune cells whil suppressing immunosuppressive cells. Therefore, this work represents the combinatorial potency of TMA‐NPs and X‐rays on large tumor regression through strengthened STING‐mediated radioimmunotherapeutics.