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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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