Mitochondrial-targeted photodynamic therapy combined with TGF-β inhibition potentiates anti-PD-1 therapy in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, marked by extensive stromal fibrosis and a profoundly immunosuppressive, immune-excluded tumor microenvironment (TME) that hampers the efficacy of immune checkpoint blockade. Although photodynamic therapy (PDT) can induce immunogenic cell death (ICD) and stimulate anti-tumor immunity, its effectiveness against PDAC is limited by insufficient immune activation and persistent stromal-mediated immunosuppression. To address these challenges, we develop a liposomal nanodrug that co-encapsulates a mitochondrial-targeted photosensitizer (MP) and a TGF-β receptor inhibitor (LY2109761) to synergize PDT with PD-1 checkpoint blockade. MP selectively accumulates in mitochondria and, upon light activation, amplifies mitochondrial reactive oxygen species production, inducing mitochondrial damage. This damage triggers the release of mitochondrial DNA and damage-associated molecular patterns, activating the STING pathway and eliciting potent ICD and anti-tumor immune responses. Simultaneously, liposome-mediated delivery of LY2109761 mitigates stromal desmoplasia and reverses TGF-β-driven immune suppression, enhancing effector T cell infiltration and activity. In murine PDAC models, this dual-action strategy transforms the immune-cold TME into an immune-inflamed phenotype, sensitizing tumors to PD-1 therapy and leading to pronounced tumor regression and prolonged survival. Our findings present a promising nanodrug-based approach to remodel the fibrotic and immunosuppressive TME of PDAC and enhance immunotherapeutic outcomes.