2. Academic Validation
  3. Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice

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

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. michaelb@ekmd.huji.ac.il.
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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