Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance

Cancer Cell. 2022 Oct 10;40(10):1207-1222.e10. doi: 10.1016/j.ccell.2022.08.012. Epub 2022 Sep 8.


How glucose metabolism remodels pro-tumor functions of tumor-associated macrophages (TAMs) needs further investigation. Here we show that M2-like TAMs bear the highest individual capacity to take up intratumoral glucose. Their increased glucose uptake fuels hexosamine biosynthetic pathway-dependent O-GlcNAcylation to promote cancer metastasis and chemoresistance. Glucose metabolism promotes O-GlcNAcylation of the lysosome-encapsulated protease Cathepsin B at serine 210, mediated by lysosome-localized O-GlcNAc transferase (OGT), elevating mature Cathepsin B in macrophages and its secretion in the tumor microenvironment (TME). Loss of OGT in macrophages reduces O-GlcNAcylation and mature Cathepsin B in the TME and disrupts cancer metastasis and chemoresistance. Human TAMs with high OGT are positively correlated with Cathepsin B expression, and both levels predict chemotherapy response and prognosis of individuals with cancer. Our study reports the biological and potential clinical significance of glucose metabolism in tumor-promoting TAMs and reveals insights into the underlying mechanisms.

Keywords: O-GlcNAc transferase; O-GlcNAcylation; cathepsin B; glucose metabolism; lysosome; metastasis; tumor-associated macrophages.

MeSH terms

  • Cathepsin B / metabolism*
  • Drug Resistance, Neoplasm
  • Glucose / metabolism
  • Hexosamines
  • Humans
  • Lysosomes
  • N-Acetylglucosaminyltransferases / metabolism
  • Neoplasms*
  • Serine
  • Tumor Microenvironment
  • Tumor-Associated Macrophages


  • Hexosamines
  • Serine
  • N-Acetylglucosaminyltransferases
  • CTSB protein, human
  • Cathepsin B
  • Glucose