The efficacy of Chimeric Antigen Receptor (CAR) T cells against solid tumours is limited by immunosuppressive factors including adenosine, which suppresses CAR T cells through activation of the A2A receptor (A2AR). We have previously demonstrated that CRISPR/Cas9 deletion of the A2AR significantly enhances the in vivo efficacy of both mouse and human CAR T cells [1]. Alternatively, CAR T cells engineered to express A1R, a receptor that signals inversely to A2AR, significantly enhanced the function of CAR-T cells. Constitutive A1R expression however promoted T cell differentiation and exhaustion leading to reduced CAR T cell persistence in vivo. To overcome this limitation, CRISPR/Cas9 homology directed repair was used to “knock-in” A1R under the control of the NR4A2 promoter, leading to precise expression of A1R only at the tumour site but not other tissues [2]. This led to effector differentiation and enhanced anti-tumour efficacy in-vivo, concomitant with improved long-term persistence. We further identified through CRISPR deletion, the transcription factor IRF8 as a major hub factor downstream of A1R signalling. Critically, IRF8 has not been previously implicated in T cell function and effector differentiation. These data provide a novel approach for rewiring T cell differentiation factors to enhance CAR T cell efficacy in solid tumours and could be utilized to deliver other ‘precision-guided’ payloads specifically to the tumour site [3].