MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

SUMMARY Loss of mitochondrial function contributes to CD8 + T cell dysfunction during persistent antigen encounter. How chronic antigen leads to this metabolic dysfunction remains unclear. Here, we show that TCR-dependent mitochondrial NADH accumulation drives production of ROS, ultimately leading to mitochondrial dysfunction. Among TCR-dependent proximal signaling components, MEK inhibition uniquely reduced nutrient uptake and mitochondrial NADH accumulation while increasing proliferation. As a result, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, we found that chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo . MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II CTD phosphorylation, reducing transcription rates at effector- and terminal-exhaustion associated genes while maintaining transcription of memory-associated genes. These findings establish MEK-dependent metabolic demand as a driver of T cell exhaustion and elucidate the role of MEK inhibition in enhancing immunotherapy efficacy.