In this study, we identify NT5E/CD73 as a direct hypoxia-responsive effector in EAC that is transcriptionally regulated by HIF1α, and we demonstrate that simultaneous disruption of HIF1α and NT5E suppresses tumor cell viability and perturbs key extracellular programs linked to immune evasion, angiogenesis, and migration. This evidence concerns the gene NT5E and neoplasm.