2. Academic Validation
  3. Extracellular vesicles from obese visceral adipose promote pancreatic cancer development and resistance to immune checkpoint blockade therapy

Extracellular vesicles from obese visceral adipose promote pancreatic cancer development and resistance to immune checkpoint blockade therapy

  • Cell Metab. 2025 Dec 2;37(12):2381-2401.e9. doi: 10.1016/j.cmet.2025.10.015.
Chunling Xue 1,  Sihan Zhao 1,  Yifan Zhou 1,  Ziming Chen 1,  Ji Liu 1,  Shuang Deng 1,  Lingxing Zeng 1,  Hongzhe Zhao 1,  Zilan Xu 1,  Mei Li 2,  Xiaowei He 1,  Shaoqiu Liu 1,  Shuang Liu 1,  Shaoping Zhang 1,  Xinyi Peng 1,  Xiaoyu Wu 1,  Ruihong Bai 1,  Lisha Zhuang 1,  Shaojia Wu 1,  Jialiang Zhang 1,  Dongxin Lin 3,  Xudong Huang 4,  Jian Zheng 5
Affiliations

Affiliations

  • 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
  • 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China; Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: lindx@cicams.ac.cn.
  • 4 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. Electronic address: huangxd@sysucc.org.cn.
  • 5 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China. Electronic address: zhengjian@sysucc.org.cn.
PMID: 41338178 DOI: 10.1016/j.cmet.2025.10.015
Abstract

Obesity is correlated with the development of multiple Cancer types, and obese patients with pancreatic ductal adenocarcinoma (PDAC) show dismal prognosis and resistance to immune checkpoint blockade (ICB) therapy. The molecular mechanism is largely unknown. Here, we show that obese visceral adipose tissues (VATs) can communicate with distant PDAC by delivering extracellular vesicles (EVs) carrying signal molecules. We reveal that PDAC cells can take VAT-EVs into their lysosomes, where EV-delivered Cathepsin A (Ctsa) stabilizes the ribonuclease Rnaset2b to produce free pseudouridine. Pseudouridine activates mast cells via increasing Reactive Oxygen Species (ROSs) and decreasing H3K27me3 modification at the gene promoter. Activated mast cells inhibit CD8+ T cell activity, forming an immunosuppressive tumor microenvironment that enhances Cancer progression. Animal experiments indicate that Ctsa knockdown effectively enhances ICB efficacy on PDAC. Our study uncovers a VAT-EV CTSA-pseudouridine-mast cell axis connecting obesity and Cancer, which holds promise for developing new therapeutic strategies for obesity-related cancers.

Keywords

CSTA; mast cell; obesity; pancreatic cancer; pseudouridine.

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