NK cell protection from tumor metastases is a critical feature of the host immune response to cancer, but various immunosuppression mechanisms limit NK cell effector function. The ectoenzyme, CD39, expressed on tumor-infiltrating myeloid cells, granulocytes and lymphocytes, including NK cells, converts extracellular ATP (eATP) into AMP and, thus, potentially suppresses eATP-mediated pro-inflammatory responses. A CD39-targeting monoclonal antibody (mAb) that inhibits the mouse ectoenzyme CD39 suppressed experimental and spontaneous metastases in a number of different tumor models and displayed superior anti-metastatic activity compared with the CD39 inhibitor POM1 and inhibitors and mAbs that block other members of the adenosinergic family (e.g., A2AR, CD73). The anti-metastatic activity of anti-CD39 was NK cell- and IFNgamma-dependent, and anti-CD39 enhanced the percentage and quantity of IFNgamma produced and CD107a expression in lung-infiltrating NK cells post tumor challenge and anti-CD39 therapy. Using conditional Cd39 gene-targeted mouse strains and adoptive NK cell transfers, we showed that CD39 expressed on bone marrow-derived myeloid cells was essential for anti-CD39's anti-metastatic activity, but NK cell expression of CD39 was not critical. The eATP receptor P2X7 and the NALP3 inflammasome, including downstream IL18, were critical in the mechanism of action of anti-CD39, and the frequency of P2X7 and CD39 co-expressing lung alveolar macrophages were specifically reduced one day after anti-CD39 therapy. The data provide a mechanism-of-action involving NK cells and myeloid cells, and anti-CD39 combined with anti-PD-1, NK cell activating cytokines IL15 or IL2, or an inhibitor of A2AR to effectively suppress tumor metastases.