Chimeric Antigen Receptor T cell (CAR T) immunotherapy has been remarkably successful in the treatment of B-Cell Acute Lymphoblastic Leukaemia (B-ALL). However, beyond haematological malignancies, CAR T cells have been ineffectivein 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 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 signaling by dephosphorylating JAK-1, JAK-3 and their target substrates STAT-1, -3 and -5 in a cell context-dependent manner(Simoncic, Lee-Loy et al. 2002, ten Hoeve, de Jesus Ibarra-Sanchez et al. 2002, Wiede, Shields et al. 2011, Wiede, La Gruta et al. 2014). Since CARs signal via LCK, and cytokine signalling is critical for CAR T cell function,we postulated that inhibiting PTPN2 mightbolster 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 of CAR T cellsin vitroand in vivo.