Chimeric antigen receptor (CAR) T cell therapy has been revolutionary for the treatment of haematological malignancies, but often fails to show therapeutic benefit for the treatment of solid cancers. This is in part due to the immunosuppressive microenvironment that gives rise to exhausted, poorly persisting and metabolically dysfunctional T cells. Clinical studies looking into the phenotype of CAR T cells revealed a stem-like CAR T cell product to be more resistant to immunosuppression in the tumor, and to be associated with better therapeutic outcomes. In this study we aimed to identify novel epigenetic regulators that play a role in T cell exhaustion or persistence by means of a CRISPR/Cas9 knockout screen of naïve human T cells. From this screen we identified HIC1 as the top hit and confirmed that knockout of HIC1 could increase the stem-like phenotype of CAR T cells both in vitro and ex vivo, while their cytotoxic capacity was maintained. When tested in vivo, knockout of HIC1 in CAR T cells resulted in strongly improved tumor control over conventional CAR T cells in multiple tumor models. Importantly, we found HIC1 knockout to be highly synergistic with FOXO1 overexpression, a transcription factor that has previously been described as a key factor in CAR T cell fitness and persistence. Interestingly, knockout of HIC1 in CAR T cells with FOXO1 overexpression not only increased their stem-like phenotype and metabolic fitness, but also strongly diminished activation-induced cell death, and treatment with these CAR T cells resulted in rapid tumor clearance in vivo. Therefore, this work revealed HIC1 as a promising hit for the generation of a CAR T cell product that is resistant to the immunosuppressive tumor microenvironment and as such has high translational potential to improve the efficacy of CAR T cell therapy for solid cancers.