ROS-Responsive MnO2 nanozyme co-delivering cGAMP and TGF-β inhibitor synergistically activates STING signaling and remodels the immunosuppressive thyroid cancer microenvironment.

The immunosuppressive tumor microenvironment (TME) of thyroid cancer (TC) limits the efficacy of current immunotherapies due to insufficient STING pathway activation and TGF-β–driven immune tolerance. Here, we developed a reactive oxygen species (ROS)-responsive G5-PAMAM dendrimer-encapsulated MnO2 nanozyme (GM) co-loaded with the STING agonist cGAMP and TGF-β inhibitor SB505124 (GM@cGAMP + SB) to achieve dual-pathway immune modulation. The nanozyme exhibited precise ROS-triggered release, high stability, and selective tumor activation. In vitro, GM@cGAMP + SB elevated intracellular ROS, induced mitochondrial depolarization, and promoted immunogenic cell death (ICD), characterized by CRT exposure, HMGB1 release, and ATP secretion. It effectively enhanced STING signaling and suppressed TGF-β activity in TC cells. In vivo, treatment of humanized TC xenograft mice with GM@cGAMP + SB significantly inhibited tumor growth, elevated serum TNF-α, IL-6, and IFN-γ, and promoted dendritic cell maturation and CD8⁺ T cell infiltration, while reducing CD25⁺Foxp3⁺ regulatory T cells. Single-cell RNA sequencing analysis revealed remodeled immune–stromal communication networks and activation of antitumor immunity within the TME. Importantly, GM@cGAMP + SB exhibited excellent biocompatibility and negligible systemic toxicity. In conclusion, the dual-pathway modulation achieved by the ROS-responsive MnO2 nanozyme co-loaded with a STING agonist and TGF-β inhibitor significantly boosts antitumor immunity, presenting a viable synergistic strategy for TC treatment.