O-GlcNAc transferase promotes immune evasion and immunotherapy resistance in uterine corpus endometrial cancer by targeting the glucocorticoid receptor

Background Although some tumors respond to immune checkpoint blockade therapy, checkpoint inhibitors have been unsuccessful in treating uterine corpus endometrial cancer (UCEC), and the underlying molecular mechanisms remain unclear. Methods We investigated glucose flux regulation in UCEC cells with a focus on the hexosamine biosynthesis pathway (HBP). The role of O -linked N -acetylglucosamine ( O -GlcNAc) transferase (OGT) and its interaction with the glucocorticoid receptor (GR) were examined using in vitro and in vivo models. A competitive peptide was designed to disrupt the interaction between OGT and GR. Results We found that UCEC cells direct glucose flux to the HBP. OGT, a critical enzyme for protein O -GlcNAcylation, increased programmed death ligand-1 (PD-L1) expression while decreasing major histocompatibility complex class I (MHC-I) expression, thereby promoting immune evasion and resistance to immunotherapy. Mechanistically, OGT interacted with GR, leading to O -GlcNAcylation of GR at serine 132, which required prior phosphorylation of GR. Disruptions of the OGT–GR interaction with the competitive peptide reduced GR O -GlcNAcylation, decreased PD-L1 expression, and increased MHC-I expression. This, in turn, activated CD8 + T cell-mediated immunity against tumor cells in vitro and in vivo. Conclusions Our findings reveal cross-talk between the HBP, steroid hormone pathway, and tumor immune evasion, and suggest potential strategies for sensitizing UCEC to immunotherapy.