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

T cell dysfunction during persistent antigen encounter. Here, we examined the pathways whereby chronic antigen stimulation leads to metabolic dysfunction. Chronic T cell receptor (TCR) engagement increased ATP demand, leading to mitochondrial NADH accumulation, accumulation of reactive oxygen species, and subsequent mitochondrial dysfunction. Among TCR-dependent proximal signaling components, inhibiting the kinase MEK uniquely reduced nutrient uptake and mitochondrial NADH accumulation while restoring proliferation. Accordingly, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, 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 C-terminal domain phosphorylation, reducing transcription rates at loci encoding effector- and terminal-exhaustion-associated genes while maintaining transcription of genes associated with T cell memory. Thus, MEK-dependent metabolic demand is a driver of T cell exhaustion, providing insight into how MEK inhibition enhances immunotherapy efficacy.