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Here, we present ICyM2, a carrier\u2010free and esterase\u2010responsive nanoaggregate rationally designed by covalently linking the mitochondria\u2010targeting photosensitizer ICyOH with the non\u2010nucleotide STING agonist MSA\u20102. This single\u2010molecule construct enables high drug loading, uniform nanoaggregate formation, and preferential tumor accumulation, thereby minimizing hepatic off\u2010target toxicity while allowing spatiotemporally controlled activation in the tumor microenvironment. Upon intratumoral activation, ICyOH disrupts cancer\u2010associated fibroblast (CAF)\u2013mediated stromal barriers and triggers immunogenic cell death (ICD), which facilitates deep penetration of MSA\u20102. Subsequently, MSA\u20102 amplifies ICD\u2010derived antigenic signaling, activates the STING pathway, promotes dendritic cell maturation, reprograms macrophages toward an M1\u2010like phenotype, and enhances cytotoxic T\u2010cell infiltration. In vivo, ICyM2 elicits potent tumor regression, establishes durable immune memory that suppresses lung metastasis, and converts immunologically \u201ccold\u201d tumors into \u201chot.\u201d Moreover, ICyM2 synergizes with PD\u20101 blockade to further strengthen antitumor immunity without observable systemic toxicity. Collectively, ICyM2 integrates stromal remodeling and immune activation within a single, carrier\u2010free platform, providing a clinically translatable photo\u2010immunotherapeutic strategy to overcome stromal and immune resistance in pancreatic cancer.<\/jats:p>","DOI":"10.1002\/advs.202520547","type":"journal-article","created":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T10:01:46Z","timestamp":1766829706000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["STING Agonist\u2010Modified Tumor Targeting Photosensitizer Remodels Cancer\u2010Associated Fibroblasts to Potentiate Photoimmunotherapy in Pancreatic Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Yixuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School  Nanjing 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