CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting.

ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B-cell malignancies, but its success in acute myeloid leukemia (AML) remains limited. Durable responses depend on the formation of long-lived memory T cells, whereas T cell exhaustion contributes to non-response and relapse. In patients with AML who achieved remission after cord blood transplantation, we here first observe enrichment of memory T cells with high expression of the chemokine receptor CXCR4. Next, we show that engineering CAR-T cells to co-express CXCR4 enhances their persistence and anti-leukemic activity in patient-derived xenograft models. Using single-cell profiling and metabolic analysis, we find that CXCR4 promotes memory-associated transcriptional programs, reduces exhaustion, and supports o

SUBMITTER: Itoh-Nakadai A 

PROVIDER: S-EPMC12835132 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature