Piezo‐STING Agonists Enhance Tumor Penetration and Catalytic‐immunotherapy

Abstract The cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)‐stimulator of interferon genes (STING) signaling pathway is an important innate immune pathway that has shown remarkable potential in cancer immunotherapy. However, the clinical therapeutic efficacy is limited due to insufficient penetration of STING agonists into tumors. In this study, a special piezo‐STING agonist (ZnS‐Cur@CM, Z/C@M) composed of zinc sulfide nanosheets, curcumin, and tumor cell membranes based on the principle of piezocatalytic for water splitting to generate gas is designed, which effectively reduces the intratumoral delivery resistance, markedly enhancing the penetration depth of drug into tumors. Under ultrasound, Z/C@M rapidly decomposes the tumor interstitial fluid to produce hydrogen, leading to decreased interstitial pressure and increased drug accumulation within the tumor. Additionally, the reactive oxygen species generated by piezocatalysis damage the mitochondria of tumor cells, resulting in the release of mitochondrial DNA and activation of the cGAS‐STING pathway. Moreover, the released Zn 2+ in the acidic tumor microenvironment further enhances cGAS‐STING signal transduction. The piezo‐STING agonists reduce tumor interstitial fluid pressure through piezocatalysis and improve the insufficient penetration of STING agonists within tumors, which also further activates the signaling pathway and enhances the efficacy of cancer treatment. This study provides a novel perspective on tumor immunotherapy.