Chimeric Antigen Receptor T cell (CAR T) immunotherapy has been remarkably successful in the treatment of B-Cell Acute Lymphoblastic Leukaemia. However, beyond haematological malignancies, CAR T cell therapy has been ineffective in treating solid tumours. Novel approaches for enhancing the ability of CAR T cells to combat solid tumours are urgently required. Protein tyrosine phosphatases (PTPs) are enzymes that regulate a wide range of physiological processes including metabolism, cellular growth, proliferation and differentiation by controlling tyrosine phosphorylation-dependent signalling. PTPs are key regulators of T cell signalling and contribute to the maintenance of immune tolerance. Studies from our group have shown that PTPN2 plays a pivotal role in negatively regulating T cell receptor (TCR) signalling by dephosphorylating and inactivating the Src family protein tyrosine kinase LCK (Wiede, Shields et al. 2011). PTPN2 also attenuates cytokine signalling by dephosphorylating JAK-1 and JAK-3 and their target substrates STAT-1, -3 and -5 in a cell context-dependent manner. Since CARs signal via LCK, and cytokine signalling is critical for CAR T cell function, we postulated that inhibiting PTPN2 might bolster the anti-tumour activity of CAR T cells. Here we used CRISPR-Cas9-ribonucleoprotein (RNP)-mediated genome editing to delete PTPN2 in CAR T cells. Using this approach PTPN2 was efficiently deleted in CAR T cells and the deletion of PTPN2 significantly enhanced the anti-tumour efficacy CAR T cells in vitro and in vivo.