Metabolic Reprogramming Driven by Ant2 Deficiency Augments T Cell Function and Anti-Tumor Immunity

cell activation demands a significant boost in NAD+ levels, often outpacing the capacity of oxidative phosphorylation (OXPHOS). To explore how T cells manage this metabolic stress, we created T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Ant2, which is vital for ADP/ATP exchange between the mitochondria and cytoplasm, when deleted, disrupts OXPHOS by limiting ATP synthase function and blocking NAD+ replenishment. Surprisingly, Ant2-/- naïve T cells show increased activation, proliferation, and effector functions compared to wild-type T cells. Through metabolic profiling, we find these cells adopt a metabolic state similar to that of activated T cells, with heightened mitochondrial biogenesis and anabolic processes. Inhibiting ANT pharmacologically in wild-type T cells mirrors the Ant2-/- phenotype and enhances the effectiveness of adoptive T cell therapies in cancer treatment. These results suggest that Ant2-deficient T cells bypass the usual metabolic shifts necessary for activation, leading to greater T cell function and highlighting ANT inhibition as a potential therapeutic strategy for modulating immune responses.