Abstract Failure of adoptive T cell therapies in cancer patients is linked to limited T cell expansion and persistence, even in memory-prone 41BB-(BBz)-based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR T cell stem/memory differentiation and persistence can be enhanced through epigenetic manipulation of the histone 3 lysine 9 tri-methylation (H3K9me3) pathway. Inactivation of the H3K9 tri-methyltransferase SUV39H1 enhances BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated solid tumor models up to several months after CAR T cell infusion. Single-cell transcriptomic (scRNAseq) and chromatin opening (scATACseq) analyses of tumor infiltrating CAR T cells show early reprogramming into self-renewing, stem-like populations with decreased expression of dysfunction genes in all T cell subpopulations. Therefore, epigenetic manipulation of H3K9 methylation by SUV39H1 optimizes long-term functional persistence of BBz-CAR T cells, limiting relapses and providing protection against tumor rechallenges.