Redirecting potent T cell responses against cancer by means of a Chimeric Antigen Receptor (CAR) has been very successful against Acute Lymphoblastic Leukemia and Non-Hodgkin lymphoma. Solid tumours however pose a greater challenge as they differ dramatically in the form of the immunosuppressive tumour microenvironment (TME). One mechanism of suppression is through the adenosine pathway. Binding of adenosine to A2A adenosine receptors (A2AR), which are highly expressed on T cells results in suppression of effector T cell responses. Our lab has previously shown that targeted blockade of the A2AR can improve both endogenous T cells [1] and CAR T cell efficacy [2]. This project seeks to re-engineer CAR T cells to be resistant to adenosine mediated immunosuppression in solid tumours by overexpressing the A1R and A3R alternative signalling receptors. Overexpression of the A1R and A3R in CAR T cells drive improved cytokine function in vitro. In an immunocompetent syngeneic mouse model tolerant to the human HER2 target antigen, A3R expressing anti-HER2 CAR T cell infusion results in dramatic reduction in tumour sizes and improved survival of mice bearing the E0771-HER2 breast cancer or MC38-HER2 colon adenocarcinoma cancer cell lines. This was accompanied by increased expression of effector cell markers in vivo including PD-1. Subsequently, PD-1 blockade synergized with A3R CAR T cells to further improve therapeutic efficacy. These results lend insight into the role of the A1R and A3R in CAR T cells and could lead to improved CAR T cell efficacy against solid tumours.