Inhibition of CD38 Enzymatic Activity Enhances CAR-T Cell Immune-Therapeutic Efficacy by Repressing Glycolytic Metabolism.

Chimeric antigen receptor (CAR) -T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor control partially due to CAR -T cell exhaustion and limited persistence. In this study, by performing single -cell multi-omics data analysis on patient -derived CAR -T cells, we identify CD38 as a potential hallmark of exhausted CAR -T cells, which is positively correlated with exhaustion -related transcription factors and further confirmed with in vitro exhaustion models. Moreover, inhibiting CD38 activity reverses tonic signaling- or tumor antigen -induced exhaustion independent of single -chain variable fragment design or costimulatory domain, resulting in improved CAR -T cell cytotoxicity and antitumor response. Mechanistically, CD38 inhibition synergizes the downregulation of CD38cADPR -Ca2+ signaling and activation of the CD38-NAD+-SIRT1 axis to suppress glycolysis. Collectively, our findings shed light on the role of CD38 in CAR -T cell exhaustion and suggest potential clinical applications of CD38 inhibition in enhancing the efficacy and persistence of CAR -T cell therapy.