Tumor microenvironment-responsive manganese nanoplatform amplifies cGAS-STING via metabolic-metal synergy for immunotherapy.

Metabolically deranged tumor microenvironment (TME) with compromised innate immune signaling induces severe immunosuppression and markedly blunts the efficacy of cancer immunotherapy. Activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway can boost antitumor immunotherapy, and a manganese complex, called TPE-Mn, was developed in this work. Nevertheless, the excess lactate accumulation and poor tumor-targeted delivery jointly restrict the clinical translation of Mn2+-based immune stimulation. Herein, we designed glutathione (GSH)-sensitive nanoparticles (NPMn/Syro) co-loaded with TPE-Mn and the monocarboxylate transporter 1/4 (MCT1/4) inhibitor syrosingopine (Syro) at an optimized ratio to simultaneously remodel tumor metabolism and activate innate immunity. Upon effective intratumoral accumulation, NPMn/Syro concurrently release two payloads: Syro inhibit lactate efflux and elevates intracellular lactate, while TPE-Mn disrupts mitochondrial dynamics. Collectively, these synergistic effects shift the mitochondrial fusion-fission balance toward excessive fission, leading to mitochondrial fragmentation and cytosolic mitochondrial DNA (mtDNA) leakage. The leaked mtDNA activates cGAS, while Mn2+ further amplifies the activation of the STING pathway to boost innate immune responses. Moreover, metabolic disruption and mitochondrial injury cooperatively trigger immunogenic cell death (ICD) and potentiate systemic antitumor immunity. Furthermore, combined with anti-PD-1 antibody (α-PD-1), NPMn/Syro exerts synergistic antitumor efficacy, providing a promising therapeutic strategy for clinical management of tumor. This work presents a metabolic-metal synergistic strategy to augment the cGAS-STING pathway activation and significantly reverse metabolism-mediated immunosuppressive TME.