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

T-cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generated T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, impeding NAD+ regeneration. Interestingly, Ant2-/- naive T cells exhibited enhanced activation, proliferation, and effector functions compared to wild-type controls. Metabolic profiling revealed that these cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Pharmacological inhibition of ANT in wild-type T cells recapitulated the Ant2-/- phenotype, and improved adoptive cell therapy of cancer. Our findings suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T-cell function. These results highlight the critical role of mitochondrial metabolism in regulating T-cell fate and underscore the therapeutic potential of targeting ANT for immune modulation.