biostudies-literatureUnknown15(1)Zuo Sthe National Natural Science Foundation of ChinChimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCTNature communications6155https://www.ebi.ac.uk/biostudies/studies/S-EPMC11263573biostudies-literatureC-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial.PMC11263573Shan LHuang HHan YWang GHan ZZuo STang KNiu QZhou DZong JWu TWang ZYu XSong YDuan JLi CFeng XZheng QSun XXu JDeng BTian ZPan JZhang YLing ZXu XFeng SfalseC-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial.Chimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT2024-01-01T00:00:00Z2024 Jul2026-06-02T09:09:01.058Z2025-06-01T01:17:00.834ZS-EPMC112635733903908610.1038/s41467-024-50485-9