CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.