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<p>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 MnO<sub>2</sub> 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. <i>In vivo</i>, 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 MnO<sub>2</sub> nanozyme co-loaded with a STING agonist and TGF-β inhibitor significantly boosts antitumor immunity, presenting a viable synergistic strategy for TC treatment.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • Guangming Liu,
  • Rui Li

摘要

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.

Graphical Abstract