Cancer cell CD73 loss promotes a dual inflammatory and immunosuppressive microenvironment in endometrial carcinoma.

CD73 is an emerging immunotherapy target that is overexpressed in many tumors and generates an adenosine-rich microenvironment to suppress antitumor immunity. In low-grade endometrial carcinoma (EC), CD73 expression varies, and its impact on tumor immunobiology is unknown. Using two microsatellite-stable, grade 2 endometrioid EC (G2 EECMSS) cohorts, in vitro NT5E (CD73) knockout/knockdown, and single-cell and spatial analyses, we show that cancer cell CD73 loss promotes a dual inflammatory and immunosuppressive microenvironment. Cancer cell CD73 loss was associated with increased lymphovascular space invasion and worse recurrence-free and overall survival, whereas stromal CD73 expression did not correlate with outcomes. CD73 downregulation induced proinflammatory gene expression, which strongly correlated with upregulation of immunosuppressive genes, including CD274 (PD-L1), suggesting a compensatory mechanism limiting antitumor immunity. Tumors with low cancer cell CD73 exhibited higher PD-L1 expression that correlated with increased CD3⁺ T-cell infiltration, reflecting an immune-engaged but checkpoint-restrained microenvironment. Single-cell analyses demonstrated that NT5E+ non-immune cells in immune-responsive clusters were three times less likely to express CD274. In clinically relevant low-grade EC models, functional studies confirmed that CD73 loss promoted both proinflammatory and immunosuppressive programs. These results reveal a context-specific role for CD73 in shaping the immune landscape of low-grade EC that is distinct from its function in other solid tumors.