Robust, long-lasting immune responses are elicited by memory T cells that possess properties of stem cells, enabling them to persist long-term and to permanently replenish the effector pools. Thus, stem cell-like memory T (T_SCM) cells are of key therapeutic value and efforts are underway to characterize T_SCM cells and to identify means for their targeted induction.

Here, we show that inhibition of mechanistic/mammalian Target of Rapamycin (mTOR) complex 1 (mTORC1) by rapamycin or the Wnt-β-catenin signalling activator TWS119 in activated human naive T cells leads to the induction of T_SCM cells. We show that these compounds switch T cell metabolism to fatty acid oxidation as favoured metabolic programme for T_SCM cell generation. Of note, pharmacologically induced T_SCM cells possess superior functional features as a long-term repopulation capacity after adoptive transfer. Furthermore, we provide insights into the transcriptome of T_SCM cells.

Our data identify a mechanism of pharmacological mTORC1 inhibitors, allowing us to confer stemness to human naive T cells which may be significantly relevant for the design of innovative T cell-based cancer immunotherapies.