This study examined how chronic TCR engagement drives CD8+ T cell metabolic dysfunction and terminal exhaustion, focusing on the role of MEK/ERK signaling in mitochondrial NADH accumulation, ROS generation, protein synthesis rates, and transcription — using in vitro chronic stimulation models and in vivo LCMV-Clone 13 and B16-OVA tumor models in mice.
MEK inhibition (trametinib, 1 mg/kg; mirdametinib/PD0325901, 100 nM) uniquely reduced ATP demand, ROS, and nutrient uptake while restoring T cell proliferation during chronic stimulation. MEKi-treated mice showed ~double the intratumoral antigen-experienced OT-I T cells vs. controls (p=0.0346). Mechanistically, chronic MEK activation drove global protein synthesis (the dominant ATP consumer) and RNA Pol II CTD phosphorylation, increasing nascent transcription of terminal exhaustion genes (e.g., *Havcr2*, *Lag3*, *Ifng*) while suppressing memory genes (e.g., *Tcf7*, *Foxo1*, *Sell*); MEKi reversed this pattern.
- All in vivo data are from mouse models (LCMV and B16-OVA); direct human T cell validation is absent. - Exact sample sizes per group are small (n=3–8 per group for most assays); no clinical or patient-derived data. - The study does not address optimal dosing regimens or long-term effects of MEKi on T cell function in combination with checkpoint blockade.
MEK inhibition (e.g., trametinib) may enhance anti-tumor T cell persistence by reducing metabolic exhaustion, not just by direct tumor effects — supporting rationale for combining pulsatile MEKi with checkpoint blockade in clinical trials. Clinicians should consider that MEKi's benefit in immunotherapy may be partly T cell-intrinsic, independent of tumor cell BRAF/MEK mutation status.
