Jingjing Wang

Advances in Antibody–Drug Conjugates for Endometrial Cancer

Abstract The treatment of advanced endometrial cancer is clinically challenging, prompting the exploration of innovative therapeutic strategies such as antibody-drug conjugates (ADC). ADCs, which include mAbs, cytotoxic components, and linkers, demonstrate robust targeting, cytotoxicity, and manageable adverse effects. To provide a thorough understanding of the status of research, this review elucidates promising therapeutic targets in endometrial cancer, such as HER2, folate receptor α, and trophoblast surface antigen-2, and summarizes preclinical and clinical trial data on related ADC drugs in endometrial cancer. We also discuss the toxicity of ADC drugs. Most adverse events arise from cytotoxic components such as microtubule inhibitors and topoisomerase inhibitors. The ocular toxicity may be mainly related to off-target effects of monomethyl auristatin F/DF4 payloads. Interstitial lung disease is a serious adverse event, mainly caused by antibodies, and most of them are of grade 1 to 2 toxicity. Among them, anti-HER2 ADC–induced interstitial pneumonia is commonly dose-dependent. Moreover, we identified potential new targets for endometrial cancer treatment and explored strategies to overcome ADC resistance, such as choosing combination therapy or developing a new generation of ADC drugs. Continuous research and innovation in this field hold promise for improving the survival and overall quality of life of patients with advanced endometrial cancer.

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.