Linperlisib enhances MUC1-Tn CAR T cell efficacy by inhibiting EGR1/DUSP2 axis to prevent CAR T cell exhaustion.

Chimeric antigen receptor (CAR) T cell therapy demonstrates suboptimal efficacy in T-cell acute lymphoblastic leukemia (T-ALL), largely due to target-mediated fratricide from shared antigen expression and effector T cell exhaustion. The Mucin1-Thomsen-nouvelle (MUC1-Tn) antigen is overexpressed in various malignancies, including T-ALL. In this study, we confirmed MUC1-Tn protein expression in T-ALL cell lines and primary patient-derived bone marrow cells and subsequently developed MUC1-Tn-targeted CAR T cells. These CAR T cells effectively lysed T-ALL cells in both in vitro cytotoxicity assays and xenograft models. Given the critical role of the PI3Kδ signaling pathway in modulating T-cell function and tumor immunosuppression, we combined MUC1-Tn CAR T cells with the PI3Kδ inhibitor linperlisib. Linperlisib enhanced the anti-leukemic efficacy and persistence of MUC1-Tn CAR T cells. This was associated with reduced T cell exhaustion marker expression, decreased proportions of terminally differentiated cells, and sustained tumor control upon rechallenge. Furthermore, linperlisib induced mitochondrial fusion and enhanced respiratory capacity in CAR T cells. Mechanistically, this enhanced persistence was attributed to linperlisib-mediated suppression of Dual Specificity Phosphatase 2 (DUSP2) and its upstream transcription factor Early Growth Response 1 (EGR1).