Inhibitory Microenvironment Remodeling Enhances STING Activation for Solid Tumor Immunotherapy

Abstract The immunomodulatory effect of the interferon gene‐stimulating factor (STING) pathway makes it an important target for tumor immunotherapy, which, however, suffers from the easy degradation and deteriorated stimulatory capacity of current STING agonists in the solid tumor microenvironment. Herein, a nanocomposite medicine， MLAP， is constructed by intercalating STING agonist ADU‐S100 into Mn‐doped layered double hydroxide, which is capable of modulating the immune microenvironment of solid tumors to enhance STING activation. Importantly, the intercalation in the interlayer structure enhances the intracellular permeability of STING agonists, meanwhile, the activation of the STING pathway by ADU‐S100 is amplified by the sensitizing effect of Mn 2+ . In addition, the moderate alkalinity of MLAP neutralizes the acidity of the tumor microenvironment and catalyzes the decomposition of hydrogen peroxide to produce oxygen, rectifying the acidic and hypoxia immunosuppressive microenvironment and thus strengthening the immune activation efficacy of STING agonists. This work provides an excellent carrier for STING agonists, which not only improves the bioavailability of STING agonists but also remodels the immune microenvironment for boosted solid tumor immunotherapy.