biostudies-literaturePrinzing BNIAID NIH HHSNINDS NIH HHSNCI NIH HHSeabh0272https://www.ebi.ac.uk/biostudies/studies/S-EPMC8733956biostudies-literatureUnknown13(620)Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined. Here, we report that exhaustion of human CAR T cells occurs through an epigenetic repression of the T cell’s multipotent developmental potential. Deletion of the de novo DNA methyltransferase 3 alpha (DNMT3A) in T cells expressing first- or sScience translational medicineDeleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity.PMC8733956R01 NS106379R00 CA256262P30 CA021765R01 AI114442R01 NS121249F31 CA250401R01 CA173750K99 CA256262R01 CA237311R50 CA211481U01 AI157189Yi ZLangfitt DMHaydar DZebley CCBrown CPruett-Miller SMTsai SQVogel PCrawford JCYoungblood BAnido AAFan YKrenciute GPark JJZhou SGottschalk SNguyen PLazzarotto CRPetersen CTBoi SKPrinzing BBell MDeRenzo CAlli SRiberdy JMVelasquez MPHouke HfalseDeleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity.Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined. Here, we report that exhaustion of human CAR T cells occurs through an epigenetic repression of the T cell’s multipotent developmental potential. Deletion of the de novo DNA methyltransferase 3 alpha (DNMT3A) in T cells expressing first- or s2021-01-01T00:00:00Z2021 Nov2025-04-26T13:03:24.581Z2025-02-19T04:07:26.205ZS-EPMC87339563478807910.1126/scitranslmed.abh0272