Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice

  • Nat Commun. 2025 May 8;16(1):4292. doi: 10.1038/s41467-025-59310-3.
Omri Yosef  1 ,  Leonor Cohen-Daniel  1 ,  Oded Shamriz  1 ,  Zahala Bar-On  1 ,  Wajeeh Salaymeh  1 ,  Amijai Saragovi  1 ,  Ifat Abramovich  2 ,  Bella Agranovich  2 ,  Veronika Lutz  3 ,  Joseph Tam  4 ,  Anna Permyakova  4 ,  Eyal Gottlieb  5 ,  Magdalena Huber  3 ,  Michael Berger  6
Affiliations
  • 1. The Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
  • 2. Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
  • 3. Institute of Systems Immunology, Philipps University of Marburg, Marburg, Germany.
  • 4. Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
  • 5. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6. The Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. [email protected].
PMID: 40341170 DOI: 10.1038/s41467-025-59310-3
Abstract

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 generate 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, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of Cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation.

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