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  3. The hexosamine biosynthetic pathway drives tumor immune evasion via translational control of PD-L1 at the elongation level

The hexosamine biosynthetic pathway drives tumor immune evasion via translational control of PD-L1 at the elongation level

  • Cell Rep. 2025 Sep 23;44(9):116249. doi: 10.1016/j.celrep.2025.116249.
Bo Liu 1,  Yingying Wu 2,  Anyi Xiang 3,  Yiyi Yu 4,  Shushu Song 5,  Ying Zhang 6,  Jianxin Gu 5,  Haojie Lu 7,  Ping Xu 8,  Fenglin Liu 9,  Yuanyuan Ruan 10
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Second Department of Gastric Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China.
  • 2 Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 3 Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 5 NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 6 NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: ying@fudan.edu.cn.
  • 7 NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: luhaojie@fudan.edu.cn.
  • 8 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address: xuping_bprc@126.com.
  • 9 Second Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. Electronic address: fenglinliu@hotmail.com.
  • 10 NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: yuanyuanruan@fudan.edu.cn.
PMID: 40938752 DOI: 10.1016/j.celrep.2025.116249
Abstract

Cancer cells reprogram cellular energetics to drive tumorigenesis and escape immunosurveillance. Nevertheless, how this is molecularly connected remains largely undefined. The hexosamine biosynthetic pathway (HBP) serves as a critical metabolic node in Cancer cells that provides the basis for protein glycosylation. Herein, we show that HBP flux inhibition by knocking out its rate-limiting enzyme GFAT1 suppressed tumor growth and stimulated cytotoxic CD8+ T lymphocyte infiltration in a colorectal Cancer model. GFAT1 induced the expression of the immune checkpoint PD-L1 at the translational level by bypassing signal peptide-mediated translation elongation arrest. Proteomic and glycoproteomic screening indicated that GFAT1 facilitated the N-linked glycosylation and protein expression of Integrin α2/α3 subunits, leading to FAK activation and elongation factor eEF1A2 upregulation. Pharmacological inhibition of HBP noticeably enhanced the efficacy of immune checkpoint blockade in vivo. Together, these findings unravel how Immune Checkpoint Proteins are manipulated by metabolic dysregulation, which can be exploited as metabolic vulnerability for improving immunotherapies.

Keywords

CP: Cancer; PD-L1; glycosylation; hexosamine biosynthetic pathway; immune evasion; protein synthesis.

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