Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression ofPRDM1, encoding the BLIMP1 transcription factor, defined highly potentTCF7[encoding T cell factor 1 (TCF1)]–expressing CD8+CAR T cells, whereas enrichment ofHAVCR2[encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]–expressing CD8+T cells with elevatedPRDM1was associated with poor outcomes.PRDM1knockout promotedTCF7-dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting ofPRDM1deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)–driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation ofNR4A3and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout ofPRDM1andNR4A3skewed CAR T cell phenotypes away from TIM-3+CD8+and toward TCF1+CD8+to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved withPRDM1andNR4A3single knockout alone. These data underscore dual targeting ofPRDM1andNR4A3as a promising approach to advance adoptive cell immuno-oncotherapy.