Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8 + T cells.

eEF-2K has important roles in stress responses and cellular metabolism. We report here a previously unappreciated but critical role of eEF-2K in regulating the fate and cytocidal activity of CD8 + T cells. CD8 + T cells from eEF-2K KO mice were more proliferative but had lower survival than their wild-type counterparts after their activation, followed by occurrence of premature senescence and exhaustion. eEF-2K KO CD8 + T cells were more metabolically active and showed hyperactivation of the Akt-mTOR-S6K pathway. Loss of eEF-2K substantially impaired the activity of CD8 + T cells. Furthermore, the antitumor efficacy and tumor infiltration of the CAR-CD8 + T cells lacking eEF-2K were notably reduced as compared to the control CAR-CD8 + T cells. Thus, eEF-2K is critically required for sustaining the viability and function of cytotoxic CD8 + T cells, and therapeutic augmentation of this kinase may be exploited as a novel approach to reinforcing CAR-T therapy against cancer.