MTFR2 promotes VDAC1 oligomerization to reprogram BCAA metabolism in tumor cells to polarize TAMs in LUAD

  • Cell Death Dis. 2026 May 20. doi: 10.1038/s41419-026-08871-2.
Yutong Ge  #  1 ,  Tao Yu  #  1 ,  Shaokun Yu  2 ,  Ao Sun  1 ,  Shiyu Zhang  3 ,  Meiling Zhang  1 ,  Qian Wang  1 ,  Jia Liu  4 ,  Xuan Zhang  1 ,  Lulin Zeng  1 ,  Kaihua Lu  5
Affiliations
  • 1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 2. Department of Oncology Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China.
  • 3. Department of Respiratory and Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 4. Department of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 5. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 42161922 DOI: 10.1038/s41419-026-08871-2
Abstract

Tumor-associated macrophages (TAMs) enriched in tumor microenvironment (TME) promote immune evasion and poor prognosis. Mitochondrial dysfunction, especially branched-chain amino acid (BCAA) metabolic reprogramming, has been confirmed to be involved in regulating TAMs function. The mitochondria-related protein MTFR2 was significantly upregulated in LUAD and closely associated with reduced survival. We conducted flow cytometry, multiplex immunofluorescence, immunohistochemistry on LUAD tissues, combined with analysis of public single-cell Sequencing datasets, to characterize the TME features under MTFR2 dysregulation. Transcriptomics, metabolomics, and proteomics analyses revealed BCAA metabolic reprogramming, which was driven by MTFR2 binding to Leu125 within the β8 strand of VDAC1 and promoting its oligomerization. This interaction triggered mtDNA release into the cytoplasm, activating the TLR9-NF-κB pathway to upregulate BCAT1. Elevated concentrations of BCAA metabolites such as α-ketoisocaproate (KIC) and α-keto-β-methylvalerate (KMV) in the TME promoted M2 polarization and infiltration of TAMs by in vitro co-culture, 3D spheroid, and Organoid models, and polarized M2 macrophages reciprocally promoted LUAD progression. Our findings establish a LUAD associated MTFR2-VDAC1-BCAT1 axis regulating the BCKAs-M2 axis in TAMs. Notably, targeting BCAT1 or depleting macrophages blocked this loop, offering a potential combination therapy for LUAD.

Products