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

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. [Display omitted] •M2-like TAMs bear highest capacity to take up intratumoral glucose among immune cells•Increased glucose uptake in M2-like TAMs fuels HBP for protein O-GlcNAcylation•Lysosomal OGT mediates Cathepsin B O-GlcNAcylation to elevate its mature form•OGT in TAMs promotes tumor metastasis and chemoresistance through Cathepsin B Shi et al. show that M2-like tumor-associated macrophages (TAMs) bear the highest glucose uptake ability. Cathepsin B O-GlcNAcylation mediated by lysosomal OGT is the major effector downstream of glucose uptake by TAMs promoting tumor metastasis and chemoresistance. OGT expression in TAMs correlates with response to chemotherapy in individuals with colon cancer.