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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\n                    <jats:sup>+<\/jats:sup>\n                    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\u207a TILs. Along with in vitro experiments, we identified the importance of BCAAs for activation and differentiation of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. In addition, BCAA metabolism was related to response to PD-1 blockade in not subcutaneous but intrahepatic mouse model\u2013specific manner. Actually, public dataset analyses revealed that high expression of\n                    <jats:italic>BCAT1<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1038\/s41388-026-04023-0","type":"journal-article","created":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T12:15:41Z","timestamp":1792239341000},"page":"5035-5047","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Liver-specific amino acid metabolism impacts on efficacy of cancer immunotherapy"],"prefix":"10.1038","volume":"45","author":[{"given":"Yuma","family":"Fukumoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8866-0684","authenticated-orcid":false,"given":"Fumiaki","family":"Mukohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momoko","family":"Iwatsuru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2627-8524","authenticated-orcid":false,"given":"Youki","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Kanzaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadahisa","family":"Ogasawara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4146-3629","authenticated-orcid":false,"given":"Masahito","family":"Kawazu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshifumi","family":"Ninomiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoya","family":"Kemmotsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joji","family":"Nagasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Toyooka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9479-6665","authenticated-orcid":false,"given":"Tsuyoshi","family":"Osawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8601-0677","authenticated-orcid":false,"given":"Takamasa","family":"Ishino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9910-0164","authenticated-orcid":false,"given":"Yosuke","family":"Togashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,17]]},"reference":[{"key":"4023_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","volume":"7","author":"JM Llovet","year":"2021","unstructured":"Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. 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S Ogasawara received honoraria from Eisai, Chugai Pharmaceutical, AstraZeneca, and Merck & Co., Inc.; consulting or advisory fees from Eisai, MSD, Chugai Pharmaceutical, and AstraZeneca; and research grants from Bayer, AstraZeneca, and Eisai outside this study. Y Togashi received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, Eisai, and MSD; and research grants from Daiichi-Sankyo, Janssen Pharmaceutical, AstraZeneca, KORTUC, Takeda and Taiho outside this study. All the other authors declare that they have no competing financial interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All patients provided written informed consent according to the Declaration of Helsinki prior to sampling. The clinical protocols for this study (protocol numbers: 3318 and 3950) were approved by the ethics review committee of Chiba University Hospital. An opt-out for analyses using their archived samples was implemented by the information disclosure document after approval by the ethics review committee of the institution (protocol number: M10169). The study protocol is registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (UMIN000047701). Patient data were anonymized and decharacterized for analysis. Mouse experiments were approved by the Animal Committee for Animal Experimentation of Okayama University (629). All experiments met the U.S. Public Health Service Policy on Humane Care and Use of Laboratory Animals.","order":2,"name":"Ethics","label":"Ethical approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}