Abstract: Chimeric antigen receptor (CAR) T cell therapy has remarkably improved the clinical outcomes of patients with hematological malignancies, over the past years. However, several limitations remain to be overcome, especially for the treatment of patients with solid tumors. Among them, growing evidence suggests that an epigenetic drift limits CAR T cell proliferation, functionality, and efficacy during chronic antigen stimulation. These epigenetic modifications alter the CAR T cell phenotype towards a more exhausted and dysfunctional state. Noteworthy, some of these modifications are partly reversible, and several studies revealed that targeting epigenetic factors such as Tet methylcytosine dioxygenase 2 (TET2), or DNA methyltransferase 3 alpha (DNMT3A), can boost the CAR T cell efficacy against tumors by prolonging their lifespan during sustained antigen exposure. In the present study, we have evaluated the functionality of T/CAR-T cells specifically invalidated for another epigenetic factor named Retinoid-Inducible Nuclear Factor (RINF), encoded by the CXXC5 gene. The consequences of RINF disruption in human primary T cells and CAR T cells by shRNA lentiviral tools or CRISPR/Cas9 were monitored on cells cultured ex vivo, under repeated stimulation as well as in vivo in solid tumor-bearing immune-deficient mice. Interestingly, CAR T cells engineered to ablate RINF exhibited enhanced in vivo antitumor efficacy in both subcutaneous and orthotopic lung carcinoma models (human A549 cell line). This improvement correlated with increased numbers and enhanced functionality of a CD8-positive population of CAR T cells in the tumor. Our data suggested that RINF mediates a phenotype conversion in CAR T cells and that RINF disruption ameliorates CAR T cell functionality, thereby providing a new promising epigenetic target for future clinical CAR T cell therapy.