We found that during prolonged tumor antigen exposure, several exhaustion-related transcription factors, including Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3), were reciprocally upregulated in PRDM1-deficient CAR T-cells and drove epigenetically programmed T-cell dysfunction in a Nuclear factor of activated T-cells (NFAT)-dependent manner. The gene discussed is PRDM1; the disease is neoplasm.