MEK inhibition reprograms CD8⁺ T lymphocytes into memory stem cells with potent antitumor effects

Regenerative stem cell-like memory (T_SCM) CD8⁺ T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T_SCM that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced T_SCM cells exhibited plasticity and loci-specific profiles similar to bona fide T_SCM isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8⁺ T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8⁺ T cell reprogramming into T_SCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.