STING Agonist‐Modified Tumor Targeting Photosensitizer Remodels Cancer‐Associated Fibroblasts to Potentiate Photoimmunotherapy in Pancreatic Cancer

ABSTRACT Pancreatic cancer (PC) features dense stromal barriers and profound immune exclusion, rendering it largely unresponsive to immunotherapy. Here, we present ICyM2, a carrier‐free and esterase‐responsive nanoaggregate rationally designed by covalently linking the mitochondria‐targeting photosensitizer ICyOH with the non‐nucleotide STING agonist MSA‐2. This single‐molecule construct enables high drug loading, uniform nanoaggregate formation, and preferential tumor accumulation, thereby minimizing hepatic off‐target toxicity while allowing spatiotemporally controlled activation in the tumor microenvironment. Upon intratumoral activation, ICyOH disrupts cancer‐associated fibroblast (CAF)–mediated stromal barriers and triggers immunogenic cell death (ICD), which facilitates deep penetration of MSA‐2. Subsequently, MSA‐2 amplifies ICD‐derived antigenic signaling, activates the STING pathway, promotes dendritic cell maturation, reprograms macrophages toward an M1‐like phenotype, and enhances cytotoxic T‐cell infiltration. In vivo, ICyM2 elicits potent tumor regression, establishes durable immune memory that suppresses lung metastasis, and converts immunologically “cold” tumors into “hot.” Moreover, ICyM2 synergizes with PD‐1 blockade to further strengthen antitumor immunity without observable systemic toxicity. Collectively, ICyM2 integrates stromal remodeling and immune activation within a single, carrier‐free platform, providing a clinically translatable photo‐immunotherapeutic strategy to overcome stromal and immune resistance in pancreatic cancer.