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Cancer Cell CD73 Loss Promotes a Dual Inflammatory and Immunosuppressive Microenvironment in Endometrial Carcinoma

Year: 2026

Type: article

Abstract: 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, CD73 expression varies, and its impact on tumor immunobiology is unknown. Using two microsatellite-stable, grade 2 endometrioid endometrial carcinoma 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 pro-inflammatory 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+ nonimmune cells in immune-responsive clusters were three times less likely to express CD274. In clinically relevant low-grade endometrial carcinoma models, functional studies confirmed that CD73 loss promoted both pro-inflammatory and immunosuppressive programs. These results reveal a context-specific role for CD73 in shaping the immune landscape of low-grade endometrial carcinoma that is distinct from its function in other solid tumors. SIGNIFICANCE: Unlike most cancers, in which CD73 drives immunosuppression via overexpression, we show that cancer cell CD73 loss promotes an inflammatory yet compensatory immunosuppressive microenvironment in low-grade endometrial carcinoma, revealing a context-specific role. CD73 loss in endometrial carcinoma therefore may be as immunologically significant as its overexpression in other cancers.

Source: Cancer Research Communications

DOI: 10.1158/2767-9764.crc-26-0167