Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity

  • Nat Cell Biol. 2025 Aug;27(8):1357-1366. doi: 10.1038/s41556-025-01716-8.
Xian Du  #  1 ,  Wenyan Li  #  2 ,  Guiying Li  #  3 ,  Chenyue Guo  #  1 ,  Xuyi Tang  1 ,  Rujuan Bao  1 ,  Runchang Li  4 ,  Haiyan Huang  5 ,  Shuiyu Xu  5 ,  Xiaoyan Yu  1 ,  Qiaoqiao Han  1 ,  Jie Wan  1 ,  Song Li  1 ,  Jiayuan Sun  4 ,  Ren Zhao  5 ,  Youqiong Ye  1 ,  Qiang Gao  6 ,  Zhi-Yu Ni  7 ,  Xingang Cui  8 ,  Qiang Zou  9
Affiliations
  • 1. Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Department of Nephrology, Affiliated Hospital of Hebei Engineering University, Handan, China.
  • 4. Department of Respiratory Endoscopy and Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Department of Liver Surgery and Transplantation and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 7. Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, China. [email protected].
  • 8. Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 9. Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 40781141 DOI: 10.1038/s41556-025-01716-8
Abstract

Dietary nutrients are inextricably linked to antitumour immune responses. However, the effect of diet-derived galactose on antitumour immunity remains unclear. Here we show that dietary galactose augments CD8+ T cell immunity to suppress tumour progression. High-galactose feeding drives hepatocyte-derived insulin-like growth factor binding protein 1 (IGFBP-1) production, thus restraining IGF-1 signalling-dependent T cell exhaustion. IGF-1 receptor (IGF-1R) deficiency in T cells potentiates antitumour CD8+ T cell responses and phenocopies high-galactose feeding by preventing T cell exhaustion. Circulating galactose reprograms hepatocyte metabolism to inactivate mTORC1, thereby inducing the production of IGFBP-1 to boost CD8+ T cell function. Furthermore, patients with Cancer who have high plasma IGFBP-1 levels exhibit blocked T cell exhaustion and enhanced T cell responses in tumour tissues. These findings reveal that dietary galactose specifically elicits potent antitumour CD8+ T cell responses by facilitating hepatocyte-derived IGFBP-1 production, providing insights into the development of more effective immunotherapies against cancers.

Products