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  3. Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates pancreatic ductal adenocarcinoma development

Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates pancreatic ductal adenocarcinoma development

  • Cell Metab. 2025 Sep 2;37(9):1907-1925.e14. doi: 10.1016/j.cmet.2025.07.008.
Yihao Liu 1,  Jiayu Lin 1,  Zhengwei Yu 2,  Xueying Li 3,  Xueqi Lv 3,  Pengyi Liu 1,  Xiuqiao Sun 2,  Zhen Zhang 2,  Xia Gao 2,  Keyan Sun 2,  Dan Li 1,  Jingfeng Li 1,  Yang Liu 1,  Yu Jiang 1,  Siyi Zou 1,  Jianping Lin 4,  Baofa Sun 5,  Da Fu 6,  Baiyong Shen 7
Affiliations

Affiliations

  • 1 Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Pancreatic Neoplasms Translational Research, Research Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiaotong University, Shanghai 200025, China.
  • 2 Shanghai Key Laboratory of Pancreatic Neoplasms Translational Research, Research Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 4 College of Pharmacy, Nankai University, Tianjin 300353, China.
  • 5 State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: sunbf@nankai.edu.cn.
  • 6 Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Pancreatic Neoplasms Translational Research, Research Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiaotong University, Shanghai 200025, China. Electronic address: fuda@shsmu.edu.cn.
  • 7 Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Pancreatic Neoplasms Translational Research, Research Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiaotong University, Shanghai 200025, China. Electronic address: shenby@shsmu.edu.cn.
PMID: 40803319 DOI: 10.1016/j.cmet.2025.07.008
Abstract

Diabetes mellitus (DM) is a known risk factor for pancreatic Cancer, but the underlying mechanisms remain elusive. Here, we identify lactate-driven remodeling of tumor-associated Schwann cells (TASCs) as a key mediator of immunosuppression in diabetic pancreatic ductal adenocarcinoma (PDAC). Single-cell RNA Sequencing revealed a c1-Mettl16+Cd276+Nectin2+ TASC subpopulation enriched in diabetic tumors that impairs CD8+ T cell function and promotes PD-1 resistance. Mechanistically, lactate enters TASCs via MCT1/MCT4, binds METTL16, and induces K269 lactylation, enhancing m6A-dependent CTCF stabilization and transcriptional activation of immunosuppressive ligands. Targeting METTL16 restores immune surveillance and sensitizes tumors to PD-1 blockade. Retrospective analyses confirmed therapeutic benefit in patients with diabetic PDAC receiving rosuvastatin. These findings uncover a lactate-METTL16-CTCF axis that links metabolic stress to epitranscriptomic reprogramming and immune evasion, offering a promising strategy to potentiate immunotherapy in metabolically dysregulated PDAC.

Keywords

METTL16; anti-tumor immune response; diabetes-associated pancreatic cancer; lactate sensing; rosuvastatin, anti-PD-1; tumor-associated Schwann cells.

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