Abstract
Background: Endometrial cancer (EC) remains a major gynecologic malignancy with limited biomarkers for risk stratification. While killer cell lectin-like receptor G2 (KLRG2) exhibits oncogenic properties in other cancers, its clinical significance and mechanistic roles in EC are unknown. This study aims to systematically characterize KLRG2 expression in EC, evaluate its prognostic significance, decipher underlying molecular mechanisms, and explore its role in tumor immune microenvironment regulation. Methods: We performed integrated multi-omics analyses using TCGA-UCEC (n = 552), GTEx, and GEO cohorts (GSE106191), complemented by qPCR validation (14 EC vs. 14 normal samples). Prognostic models were constructed via Cox regression and time-dependent ROC analysis. Epigenetic regulation was assessed through methylation profiling (UALCAN/MethSurv), and immune correlations were evaluated using TIMER/ESTIMATE algorithms. Results: KLRG2 was significantly overexpressed in EC tissues compared to normal endometrium (p < 0.001), validated by immunohistochemistry and qPCR. High KLRG2 expression independently predicted worse overall survival (HR = 3.08, 95% CI = 1.92-4.96) and progression-free interval (HR = 1.98, 95% CI = 1.37-2.87). Furthermore, elevated KLRG2 levels were significantly associated with advanced-stage disease (p < 0.001), deep myometrial invasion (p < 0.05), and high-grade histology (p < 0.001). Mechanistically, promoter hypomethylation was associated with KLRG2 overexpression (p < 0.001), while hypermethylation at three CpG sites (cg04915254, cg04520485, cg23104233) correlated with poor prognosis. Functional enrichment linked KLRG2 to cell cycle checkpoints and G Protein-Coupled Receptor signaling. Immune profiling revealed cytotoxic lymphocyte depletion (CD8+ T cells: Spearman's ρ = -0.247, p < 0.001; NK CD56bright cells: Spearman's ρ = -0.276, p < 0.001) and Th2 polarization (Spearman's ρ = 0.117, p = 0.006). Conclusions: This comprehensive EC study establishes KLRG2 as a dual diagnostic/prognostic biomarker and immunomodulatory target. These findings provide a rationale for developing KLRG2-directed therapies to counteract tumor-intrinsic proliferation and microenvironmental immune suppression. Future single-cell analyses are warranted to dissect KLRG2-mediated tumor-immune crosstalk.