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

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

  • J Nanobiotechnology. 2025 Nov 27;23(1):748. doi: 10.1186/s12951-025-03795-z.
Shijin Xu # 1 2,  Naidi Yang # 3,  Fangning Du # 3,  Ziying Zhang 1 2,  Yin Zhang 4 2,  Yixuan Zhang 4 2,  Jiawei Liang 4 2,  Yihan Zhao 4 2,  Jiajun Zhang 1 2,  Ziwei Zhang 4,  Xiaoxuan Han 4,  Zena Chen 3,  Zhiqiang Zhou 3,  Shu Zhang 5 6 7,  Lin Li 8 9,  Ying Lv 10 11 12
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China.
  • 2 Institute of Pancreatology, Nanjing University, Nanjing, 210008, China.
  • 3 State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Flexible Electronics (Future Technologies), Nanjing Tech University (NanjingTech), Nanjing, 211816, China.
  • 4 Department of Gastroenterology, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, 210008, China.
  • 5 Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China. [email protected].
  • 6 Department of Gastroenterology, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, 210008, China. [email protected].
  • 7 Institute of Pancreatology, Nanjing University, Nanjing, 210008, China. [email protected].
  • 8 State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Flexible Electronics (Future Technologies), Nanjing Tech University (NanjingTech), Nanjing, 211816, China. [email protected].
  • 9 State Key Laboratory of Flexible Electronics (LoFE) & Institute of Flexible Electronics (IFE), Xiamen University, Xiamen, 361102, China. [email protected].
  • 10 Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China. [email protected].
  • 11 Department of Gastroenterology, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, 210008, China. [email protected].
  • 12 Institute of Pancreatology, Nanjing University, Nanjing, 210008, China. [email protected].
  • # Contributed equally.
PMID: 41310702 DOI: 10.1186/s12951-025-03795-z
Abstract

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.

Keywords

Drug delivery; Pancreatic ductal adenocarcinoma; Photodynamic therapy; TGF-beta pathway; Tumor microenvironment.

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