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.