摘要
Recent studies have shown that stem cell memory T (T SCM ) cell-like properties are important for successful adoptive immunotherapy by the chimeric antigen receptor–engineered-T (CART) cells. We previously reported that both human and murineactivated T cells are converted into stem cell memory-like T (iT SCM ) cells by coculture with stromal OP9 cells expressing the NOTCH ligand. However, the mechanism of NOTCH-mediated iT SCM reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converted conventional human CAR-T cells into T SCM -like CAR-T, “CAR-iT SCM ” cells, and that mitochondrial metabolic reprogramming played a key role in this conversion. NOTCH signaling promoted mitochondrial biogenesis and fatty acid synthesis during iT SCM formation, which are essential for the properties of iT SCM cells. Forkhead box M1 (FOXM1) was identified as a downstream target of NOTCH, which was responsible for these metabolic changes and the subsequent iT SCM differentiation. Like NOTCH-induced CAR-iT SCM cells, FOXM1-induced CAR-iT SCM cells possessed superior antitumor potential compared with conventional CAR-T cells. We propose that NOTCH-or FOXM1-driven CAR-iT SCM formation is an effective strategy for improving cancer immunotherapy.