Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors. In a two-way mixed leukocyte reaction using a fully human anti-CD73, we demonstrated that Fc receptor binding augmented the production of proinflammatory cytokines. Display omitted •Functions of CD73 and A2AR are not redundant within the tumor microenvironment•Co-targeting CD73 and A2AR reduced tumor initiation, growth, and metastasis•Anti-CD73 requires Fc receptor engagement for optimal therapeutic response in mice Young et al. show that blockade of CD73 and A2AR, two components of the adenosinergic pathway, has more potent anti-tumor activity than blockade of either, partly due to increased CD73 expression in the absence of A2AR. Moreover, anti-CD73 antibodies require the FcR binding domain for optimal anti-tumor activity.