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However, the \u201cconstantly active\u201d mode of current STING agonist delivery strategies typically leads to off\u2010target toxicity and hyperimmunity. To address this critical issue, herein a metal\u2010organic frameworks\u2010based nanoagonist (DZ@A7) featuring tumor\u2010specific and near\u2010infrared (NIR) light\u2010enhanced decomposition is constructed for precisely localized STING activation and photodynamic\u2010metalloimmunotherapy. The engineered nanoagonist enabled the generation of mitochondria\u2010targeted reactive oxygen species under NIR irradiation to specifically release mitochondrial DNA (mtDNA) and inhibit the repair of nuclear DNA via hypoxia\u2010responsive drugs. Oxidized tumor mtDNA serves as an endogenous danger\u2010associated molecular pattern that activates the cGAS\u2010STING pathway. Concurrently, NIR\u2010accelerated zinc ions overloading in cancer cells further enhance the cGAS enzymatic activity through metalloimmune effects. By combining the synergistically enhanced activation of the cGAS\u2010STING 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\u2010term anti\u2010tumor immunity to suppress tumor metastasis. Therefore, the developed nanoagonist enabled NIR\u2010triggered, agonist\u2010free, and tandem\u2010amplified activation of the cGAS\u2010STING pathway, thereby offering a distinct paradigm for photodynamic\u2010metalloimmunotherapy.<\/jats:p>","DOI":"10.1002\/adma.202313029","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T06:09:00Z","timestamp":1707890940000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Decomposable Nanoagonists Enable NIR\u2010Elicited cGAS\u2010STING Activation for Tandem\u2010Amplified Photodynamic\u2010Metalloimmunotherapy"],"prefix":"10.1002","volume":"36","author":[{"given":"Xun","family":"Guo","sequence":"first","affiliation":[{"name":"Ultrasound Department of the Second Affiliated Hospital of Chongqing Medical University Chongqing Key Laboratory of Ultrasound Molecular Imaging  Chongqing 400010 P. R. 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