AbstractAlthough acute lymphoblastic leukemia (ALL) is highly responsive to chemotherapy, it is unknown how or which host immune factors influence the long-term remission of this cancer. To this end, we systematically evaluated the effects of T-cell immunity on Ph+ ALL therapy outcomes. Using a murine Arf−/−BCR-ABL1 B-cell ALL model, we showed that loss of T cells in the host drastically increased leukemia relapse after dasatinib or cytotoxic chemotherapy. Although ABL1 mutations emerged early during dasatinib treatment in both immunocompetent and immunocompromised hosts, T-cell immunity was essential for suppressing the outgrowth of drug-resistant leukemia. Bulk and single-cell transcriptome profiling of T cells during therapy pointed to the activation of type 1 immunity-related cytokine signaling being linked to long-term leukemia remission in mice. Consistent with these observations, interferon γ and interleukin 12 directly modulated dasatinib antileukemia efficacy in vivo. Finally, we evaluated peripheral blood immune cell composition in 102 children with ALL during chemotherapy and observed a significant association of T-cell abundance with treatment outcomes. Together, these results suggest that T-cell immunity plays pivotal roles in maintaining long-term remission of ALL, highlighting that the interplay between host immunity and drug resistance can be harnessed to improve ALL chemotherapy outcomes.