Single nucleus RNA sequencing analysis reveals transcriptional heterogeneity of endometrioid endometrial cancer

Endometrial cancer (EC) is the sixth most prevalent malignancy affecting women worldwide, with an increasing incidence that poses a substantial public health challenge. This study investigates the tumor microenvironment (TME) of EC, particularly high grade endometrioid endometrial cancer (HEEC), utilizing single nucleus RNA sequencing (snRNA-seq). The analysis encompassed normal endometrium (NE), HEEC, middle grade endometrioid endometrial cancer (MEEC), and low grade endometrioid endometrial cancer (LEEC). Significant cellular heterogeneity was identified within the TME, including immune cells, fibroblasts, and epithelial cells. Notably, SULF1+ NREP+ fibroblasts were significantly enriched in HEEC and associated with aggressive tumor behavior. Additionally, the study highlighted the overexpression of metabolic pathways and immune checkpoint molecules in HEEC epithelial cells, including Human Leukocyte Antigen E (HLA-E) and Killer Cell Lectin Like Receptor C1 (KLRC1), which may contribute to immune evasion and enhanced tumor aggressiveness. Identifying the EYA transcriptional coactivator and phosphatase 1 (EYA1) gene as a prospective biomarker in HEEC due to its association with poor prognosis and the enhanced proliferative and migratory capabilities of EC cells. Furthermore, analyses of cell-cell interactions revealed critical signaling pathways, such as the Leucocyte Associated Immunoglobulin Like Receptor-1 (LAIR1)- Leukocyte Immunoglobulin-like Receptor B4 (LILRB4) axis in macrophages, which may play a role in immune suppression and EEC progression. A comprehensive single-cell level characterization of the TME in EEC offers critical insights into the molecular mechanisms driving EEC progression, while identifying potential therapeutic targets. These discoveries advance our understanding of EEC pathophysiology and hold promise for the development of targeted therapies, particularly in HEEC