Single-cell transcriptomics reveals comprehensive microenvironment and highlights the dysfuntional state of NK cells in endometrioid carcinoma

Endometrioid endometrial cancer (EEC) is one of the most common gynecologic malignancies. The interaction between cancer cells and the cells in the tumor microenvironment (TME) plays a crucial role in determining disease progression and response to treatment. To better understand the diversity in the TME of ECC, we conducted a comprehensive analysis using single-cell RNA sequencing across 21 samples, including 16 ECC and 5 adjacent normal tissues. We primarily focused on tumor-infiltrating natural killer (NK) cells and their cell–cell interactions with other immune cell types. We identified a CD56dimDNAJB1 NK cells subset, which had low cytotoxic capability and high stress levels, suggesting a dysfunctional state. This subset showed strong interactions with tumor-associated macrophages through several ligand–receptor pairs. Additionally, we observed that tumor-infiltrating LAMP3+ dendritic cells may inhibit CD8+ T cells or attract regulatory T cells to the tumor area. These dendritic cells also had impaired activation effects on NK cells within the TME. Our study provides valuable insights into the role of NK cells in cancer immunity and highlights the potential of targeting specific NK cell subsets for therapeutic purposes.