In this study, we have shown that the transient and timely inhibition of LSD1 using clinically tested inhibitors during the in vitro activation and expansion of T cells reduces exhaustion and improves persistence, likely through rewiring chromatin landscapes, which consequently potentiates the antitumor efficacy of adoptively transferred T cells in both leukemia and solid tumor models. The gene discussed is KDM1A; the disease is leukemia.