A copper-engineered MnO₂ nanoplatform for potentiating STING activation and antitumor immunity in colorectal cancer.

The stimulator of interferon genes (STING) pathway plays a central role in antitumor immunity but is frequently compromised by tumor hypoxia and metabolic immunosuppression within the tumor microenvironment. Here, we developed a multifunctional nano-STING inducer based on hollow manganese dioxide (MnO₂) nanoparticles loaded with the STING agonist DMXAA and surface-modified with a copper-polyphenol nanonetwork and hyaluronic acid. Upon accumulation in tumors, this nanoplatform undergoes acid-responsive degradation, enabling controlled DMXAA release and STING activation. Concurrently, MnO₂ catalyzes tumor-derived hydrogen peroxide to generate oxygen, alleviating hypoxia and suppressing lactate production, thereby relieving lactate-mediated inhibition of STING signaling. In addition, released copper ions promote tumor cell death with immunogenic features, further facilitating immune activation. In an orthotopic colorectal cancer model, MnO₂@Cu-HA robustly activates intratumoral STING signaling, reduces immunosuppressive myeloid and regulatory T cell populations, promotes dendritic cell maturation and macrophage reprogramming, and enhances CD8⁺ T cell infiltration. Collectively, this nano-STING inducer remodels the immunosuppressive tumor microenvironment and elicits coordinated innate and adaptive antitumor immune responses, providing an effective strategy to overcome metabolic and hypoxic barriers to STING-based cancer immunotherapy.