pH-triggered Mn-ZIF8 nanoreactor enhances tumor immunotherapy by amplifying the cGAS-STING pathway through a self-reinforcing gas-metal synergy strategy

Although conventional immunotherapies have significantly transformed cancer treatment, their efficacy is still fundamentally limited by the immunosuppressive tumor microenvironment and systemic toxicity. In this study, we propose a Gas-Metal Synergy Strategy, which integrates immune activation and biosafety, by engineering a pH-responsive manganese-based zeolitic imidazolate framework (named MRPH) nanoplatform co-loaded with the nitric oxide (NO) donor RRX-001. MRPH selectively dissociates in the acidic TME, releasing Mn²⁺ and NO, which together amplify the activation of the cGAS-STING pathway through a synergistic mechanism: NO induces mitochondrial damage and the cytosolic release of mtDNA, while Mn²⁺ enhances the sensitivity of cGAS to mtDNA. Simultaneously, PEG-HA-modified nanoparticles enable tumor-targeted delivery, and this spatiotemporal coordination triggers immunogenic cell death, dendritic cell maturation, and CD8⁺ T cell infiltration, while inhibiting CD47-mediated immunosuppression and promoting tumor vascular normalization. Furthermore, our findings indicate that manganese-related genes are linked to immune modulation and tumor microenvironment remodeling in osteosarcoma patients. Both in vitro and in vivo studies demonstrate that MRPH significantly enhances gas-amplified metalloimmunotherapy. This work pioneers a low-toxicity paradigm that integrates gas therapy and metal-based immunotherapy, offering a transformative approach to solid tumor immunotherapy.