Abstract

Natural Killer (NK) cells are crucial in recognizing and eliminating tumor cells, making them pivotal in antitumor responses. Adenosine, the product of ATP hydrolysis mediated by CD39 and CD73 ectonucleotidases, has been reported to reduce the proliferation and maturation of NK cells. In this study, we investigate the expression of CD73 in NK cells and its impact on maturation, phenotype, survival, and function. Our findings reveal that while splenic NK cells express minimal levels of CD73, its expression is induced upon activation and in the tumor microenvironment upon adoptive transfer to tumor-bearing mice. Notably, within the tumor microenvironment, CD73 expression in NK cells correlates with elevated levels of PD-L1 and CD226. Accordingly, analysis of human melanoma datasets uncovers a subset of immature tumor-infiltrating NK cells expressing CD73. To further understand the role of CD73 on NK cells, we used a CD73 knockout (KO) murine model and observed that CD73-deficient NK cells display a more immature phenotype and heightened proliferative activity than wild-type (WT) NK cells. Additionally, CD73-deficient NK cells exhibit elevated levels of P2X7R and reduced CD39 expression, suggesting an increased susceptibility to ATP-induced death. Following adoptive transfer to tumor-bearing mice, CD73KO NK cells are present at a lower frequency but demonstrate similar control over tumor growth compared with WT NK cells. In conclusion, our study demonstrates the upregulation of CD73 in NK cells infiltrating tumors and underscores its role as a checkpoint regulating the functional maturation of NK cells. © The Author(s) 2025.