Decomposable Nanoagonists Enable NIR‐Elicited cGAS‐STING Activation for Tandem‐Amplified Photodynamic‐Metalloimmunotherapy

Abstract Activation of the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway has emerged as an efficient strategy to improve the therapeutic outcomes of immunotherapy. However, the “constantly active” mode of current STING agonist delivery strategies typically leads to off‐target toxicity and hyperimmunity. To address this critical issue, herein a metal‐organic frameworks‐based nanoagonist (DZ@A7) featuring tumor‐specific and near‐infrared (NIR) light‐enhanced decomposition is constructed for precisely localized STING activation and photodynamic‐metalloimmunotherapy. The engineered nanoagonist enabled the generation of mitochondria‐targeted reactive oxygen species under NIR irradiation to specifically release mitochondrial DNA (mtDNA) and inhibit the repair of nuclear DNA via hypoxia‐responsive drugs. Oxidized tumor mtDNA serves as an endogenous danger‐associated molecular pattern that activates the cGAS‐STING pathway. Concurrently, NIR‐accelerated zinc ions overloading in cancer cells further enhance the cGAS enzymatic activity through metalloimmune effects. By combining the synergistically enhanced activation of the cGAS‐STING pathway triggered by NIR irradiation, the engineered nanoagonist facilitated the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes for primary tumor eradication, which also established a long‐term anti‐tumor immunity to suppress tumor metastasis. Therefore, the developed nanoagonist enabled NIR‐triggered, agonist‐free, and tandem‐amplified activation of the cGAS‐STING pathway, thereby offering a distinct paradigm for photodynamic‐metalloimmunotherapy.