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Peer-reviewedCC BY 4.0Oncogene

Liver-specific amino acid metabolism impacts on efficacy of cancer immunotherapy

  • Yuma Fukumoto1,2
  • Fumiaki Mukohara1,2
  • Momoko Iwatsuru1
  • Youki Ueda1
  • Hiroaki Kanzaki3
  • Sadahisa Ogasawara3
  • Jason Lin4
  • Masahito Kawazu4
  • Toshifumi Ninomiya1
  • Naoya Kemmotsu1,5
  • Joji Nagasaki1
  • Shinichi Toyooka2
3 more authors
  • Tsuyoshi Osawa6,7,8
  • Takamasa Ishino1,3
  • Yosuke Togashi1,3,9,10
10 affiliations
  1. 1Department of Tumor Microenvironment, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
  2. 2Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University, Okayama, Japan
  3. 3Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
  4. 4Division of Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan
  5. 5Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
  6. 6Division of Nutriomics and Oncology, RCAST, The University of Tokyo, Tokyo, Japan
  7. 7Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
  8. 8Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
  9. 9Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan
  10. 10Kindai University Faculty of Medicine, Osaka, Japan
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Abstract

The combination immunotherapies, including those with atezolizumab and bevacizumab (Atez/Bev), have become standard therapy for hepatocellular carcinoma (HCC). However, its efficacy remains limited and reliable biomarkers are lacking. In this study, we analyzed paired tumor and background liver tissues from Atez/Bev-treated HCC patients and found that high programmed cell death-1 (PD-1) expression in CD8+ tumor-infiltrating lymphocytes (TILs) correlated with therapeutic response independent of etiology. RNA sequencing on the tumor samples revealed that the branched-chain amino acid (BCAA)-related metabolic pathway was enriched in the group with high PD-1 expression in CD8⁺ TILs. Along with in vitro experiments, we identified the importance of BCAAs for activation and differentiation of CD8+ T cells. In addition, BCAA metabolism was related to response to PD-1 blockade in not subcutaneous but intrahepatic mouse model–specific manner. Actually, public dataset analyses revealed that high expression of BCAT1, a key enzyme in BCAA metabolism, was associated with poor prognosis in HCC, but not in other cancer types. These findings suggest the importance of liver-specific BCAA metabolism in antitumor immunity and highlight the need to assess the tumor microenvironment within its organ-specific metabolic context.

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Cite

BibTeXRIS
BibTeX
@article{fukumoto2026liverspecific,
  title = {{Liver-specific amino acid metabolism impacts on efficacy of cancer immunotherapy}},
  author = {Yuma Fukumoto and Fumiaki Mukohara and Momoko Iwatsuru and Youki Ueda and Hiroaki Kanzaki and Sadahisa Ogasawara and Jason Lin and Masahito Kawazu and Toshifumi Ninomiya and Naoya Kemmotsu and Joji Nagasaki and Shinichi Toyooka and Tsuyoshi Osawa and Takamasa Ishino and Yosuke Togashi},
  journal = {Oncogene},
  year = {2026},
  month = oct,
  doi = {10.1038/s41388-026-04023-0},
  url = {https://doi.org/10.1038/s41388-026-04023-0},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Liver-specific amino acid metabolism impacts on efficacy of cancer immunotherapy
AU  - Yuma Fukumoto
AU  - Fumiaki Mukohara
AU  - Momoko Iwatsuru
AU  - Youki Ueda
AU  - Hiroaki Kanzaki
AU  - Sadahisa Ogasawara
AU  - Jason Lin
AU  - Masahito Kawazu
AU  - Toshifumi Ninomiya
AU  - Naoya Kemmotsu
AU  - Joji Nagasaki
AU  - Shinichi Toyooka
AU  - Tsuyoshi Osawa
AU  - Takamasa Ishino
AU  - Yosuke Togashi
PY  - 2026
DA  - 2026/10/17
JO  - Oncogene
DO  - 10.1038/s41388-026-04023-0
UR  - https://doi.org/10.1038/s41388-026-04023-0
AB  - The combination immunotherapies, including those with atezolizumab and bevacizumab (Atez/Bev), have become standard therapy for hepatocellular carcinoma (HCC). However, its efficacy remains limited and reliable biomarkers are lacking. In this study, we analyzed paired tumor and background liver tissues from Atez/Bev-treated HCC patients and found that high programmed cell death-1 (PD-1) expression in CD8+ tumor-infiltrating lymphocytes (TILs) correlated with therapeutic response independent of etiology. RNA sequencing on the tumor samples revealed that the branched-chain amino acid (BCAA)-related metabolic pathway was enriched in the group with high PD-1 expression in CD8⁺ TILs. Along with in vitro experiments, we identified the importance of BCAAs for activation and differentiation of CD8+ T cells. In addition, BCAA metabolism was related to response to PD-1 blockade in not subcutaneous but intrahepatic mouse model–specific manner. Actually, public dataset analyses revealed that high expression of BCAT1, a key enzyme in BCAA metabolism, was associated with poor prognosis in HCC, but not in other cancer types. These findings suggest the importance of liver-specific BCAA metabolism in antitumor immunity and highlight the need to assess the tumor microenvironment within its organ-specific metabolic context.
SN  - 0950-9232
SN  - 1476-5594
ER  -