Blocking mitochondrial leucine transamination enhances T-cell activation and improves T-cell immunity against OVA-producing EL4 lymphoma

  • Br J Cancer. 2026 May 5. doi: 10.1038/s41416-026-03455-5.
Christie M Adam  #  1 ,  Tanner J Wetzel  #  1 ,  Sheila C Erfan  1 ,  Leighton M Wheeler  2 ,  Emily E Baer  1 ,  Lindsey P Croll  1 ,  Alexander M Martin  3 ,  Taha Z Khan  1 ,  Max L Swain  1 ,  Michael P Boyer  1 ,  Elitsa A Ananieva  4
Affiliations
  • 1. Department of Biochemistry and Nutrition, Des Moines University, West Des Moines, IA, USA.
  • 2. UF Shands Hospital, University of Florida, Gainesville, FL, USA.
  • 3. Flushing Hospital Medical Center, New York, NY, USA.
  • 4. Department of Biochemistry and Nutrition, Des Moines University, West Des Moines, IA, USA. [email protected].
  • # Contributed equally.
PMID: 42086670 DOI: 10.1038/s41416-026-03455-5
Abstract

Background: T-cell metabolism is targeted by Cancer cells in an attempt to escape immune surveillance. The mitochondrial branched-chain aminotransferase, BCATm, is overexpressed in Cancer, yet its role in T-cell immunity is suggested but understudied.

Methods: C57BL/6 mice with T-cell specific-single BCATm deficiency were used to determine the impact of BCATm on T-cell function in vitro and in vivo using the murine EL4-OVA lymphoma. The studies were complemented by a transcriptomic correlation analysis of BCATm in human T cells and by using siRNA to knock-down BCATm in Jurkat T cells.

Results: The loss of BCATm from CD4+ T cells increased mitochondrial respiration but reduced the coupling between oxygen consumption and ATP synthesis, redirecting the cells to glycolysis. This compensation sustained T-cell functionality as seen by increased release of IFN-γ from CD4+ T cells or granzyme B and perforin from CD8+ T cells. Human studies further suggested that BCATm negatively affected T-cell mitochondria. While EL4-OVA tumours from T-BCATmKO mice were enriched in memory precursor CD4+ and CD8+ T cells, reduced EL4-OVA lymphoma growth was achieved in mice with T cells carrying a combined deletion of BCATm and BCATc.

Conclusions: BCATm is an immunosuppressive enzyme that may weaken T-cell performance in the lymphoma microenvironment.

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