Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A_2ARs). Herein, we have observed that CAR activation resulted in increased A_2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A_2AR antagonists or genetic targeting of A_2AR using shRNA. In 2 syngeneic HER2⁺ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A_2AR profoundly increased CAR T cell efficacy, particularly when combined with PD-1 blockade. Mechanistically, this was associated with increased cytokine production of CD8⁺ CAR T cells and increased activation of both CD8⁺ and CD4⁺ CAR T cells. Given the known clinical relevance of the CD73/adenosine pathway in several solid tumor types, and the initiation of phase I trials for A_2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types.