Adenosine is an immunosuppressive metabolite that prevents antitumor immunity and promotes metastatic dissemination. In BRAF-mutant melanoma, adenosine signaling by the A2A adenosine receptor impedes the activity of clinically approved BRAF/MEK-targeted therapies. Using preclinical melanoma models, it was found that targeting adenosine signaling in combination with BRAF/MEK inhibition provided improved tumor control and antimetastatic activity. In addition, combination BRAF/MEK treatment in melanoma patients regulates the expression of CD73, the enzyme that generates adenosine. For details, see article by Young and colleagues on page 4684.