CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown. In this study, we revealed that A 2A /A 2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A 2A −/− mice were strongly protected against tumor metastasis, indicating that host A 2A receptors enhanced tumor metastasis. A 2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A 2A blockade was due to enhanced NK cell function. Interestingly, A 2B blockade had no effect on NK cell cytotoxicity, indicating that an NK cell-independent mechanism also contributed to the increased metastasis of CD73 + tumors. Our results thus revealed that CD73 promotes tumor metastasis through multiple mechanisms, including suppression of NK cell function. Furthermore, our data strongly suggest that A 2A or A 2B antagonists may be useful for the treatment of metastatic disease. Overall, our study has potential therapeutic implications given that A 2A /A 2B receptor antagonists have already entered clinical trials in other therapeutic settings.