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

作者：Shijin Xu, Naidi Yang, Fangning Du, Ziying Zhang, Yin Zhang, Yixuan Zhang, Jiawei Liang, Yihan Zhao, Jiajun Zhang, Ziwei Zhang, Xiaoxuan Han, Zena Chen, Zhiqiang Zhou, Shu Zhang, Li Lin, Ying Lv · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03795-z · 被引用次数：6 · 研究领域：Nanoplatforms for cancer theranostics、Photodynamic Therapy Research Studies、Cancer Research and Treatments

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 nan...