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

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.