{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:17:50Z","timestamp":1790882270947,"version":"4.1.0"},"reference-count":43,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"unspecified","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP24ama221410"],"award-info":[{"award-number":["JP24ama221410"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP25ck0106793"],"award-info":[{"award-number":["JP25ck0106793"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP25fk0210131"],"award-info":[{"award-number":["JP25fk0210131"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP25fk0310537"],"award-info":[{"award-number":["JP25fk0310537"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,3,16]]},"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Atezolizumab plus bevacizumab (Atez\/Bev) has become the first-line therapy for unresectable hepatocellular carcinoma (HCC). However, reliable biomarkers to predict therapeutic response remain lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a high-throughput plasma proteomic screen using the Olink proximity extension assay to identify predictive biomarkers in 78 patients with unresectable HCC treated with Atez\/Bev. Validation was performed in an independent cohort of 89 patients. Tumorous expression of the lead candidate, carbonic anhydrase 9 (CA9), was examined using transcriptomic and single-cell analyses. Functional studies were performed in a syngeneic mouse model using Car9-overexpressing hepatoma cells, treated with anti-programmed death-ligand 1\/vascular endothelial growth factor antibodies, with or without a CA9 inhibitor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>High plasma CA9 levels were significantly associated with poor objective response rate, disease control rate, progression-free survival, and overall survival in both discovery and validation cohorts. Multivariable analysis confirmed CA9 as an independent predictor of treatment resistance and poor outcomes. Tumorous CA9 expression correlated strongly with circulating CA9 and was restricted to malignant cells. In vivo, tumors overexpressing Car9 showed resistance to Atez\/Bev therapy, characterized by reduced CD8+T\u2009cell infiltration, suppressed cytotoxic gene expression, enrichment of M2-like macrophages, and pro-angiogenic signaling. The addition of a CA9 inhibitor reversed resistance and restored antitumor efficacy of Atez\/Bev in this model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Tumor-derived circulating CA9 is a predictive biomarker and functional driver of resistance to Atez\/Bev therapy in HCC. Targeting CA9 may enhance therapeutic response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013384","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:15:26Z","timestamp":1775751326000},"page":"e013384","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Carbonic anhydrase 9 as a circulating biomarker and therapeutic target in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7658-7130","authenticated-orcid":false,"given":"Yu","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6250-1324","authenticated-orcid":false,"given":"Takahiro","family":"Kodama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Maesaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Machiko","family":"Kai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8634-2922","authenticated-orcid":false,"given":"Kazuhiro","family":"Murai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Tahata","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinobu","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9486-850X","authenticated-orcid":false,"given":"Tasuku","family":"Nakabori","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyoshi","family":"Ohkawa","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryotaro","family":"Sakamori","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka Police Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunimaro","family":"Furuta","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Ikeda Municipal Hospital, Ikeda, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Ishida","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Ikeda Municipal Hospital, Ikeda, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2482-5845","authenticated-orcid":false,"given":"Seiichi","family":"Tawara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka General Medical Center, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Yakushijin","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka General Medical Center, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasutoshi","family":"Nozaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kansai Rosai Hospital, Amagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Hosui","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka Rosai Hospital, Sakai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1668-0779","authenticated-orcid":false,"given":"Akira","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Tatsumi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naruyasu","family":"Kakita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kaizuka City Hospital, Kaizuka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhoon","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Ulsan College of Medicine, Songpa-gu, Korea (the Republic of)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moto","family":"Fukai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery I, Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinobu","family":"Taketomi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery I, Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayato","family":"Hikita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohide","family":"Tatsumi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The University of Osaka, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Takehara","sequence":"additional","affiliation":[{"name":"Kansai Rosai Hospital, Amagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"2026040909151537000_14.4.e013384.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00825-3"},{"key":"2026040909151537000_14.4.e013384.2","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1136\/gutjnl-2024-333227","article-title":"Epidemiology of gastrointestinal cancers: a systematic analysis from the Global Burden of Disease Study 2021","volume":"74","author":"Danpanichkul","year":"2024","journal-title":"Gut"},{"key":"2026040909151537000_14.4.e013384.3","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhepr.2023.100868","article-title":"Trends in hepatocellular carcinoma stage by racial\/ethnic group in the United States, 1992-2019","volume":"5","author":"Alvarez","year":"2023","journal-title":"JHEP Rep"},{"key":"2026040909151537000_14.4.e013384.4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.02745"},{"key":"2026040909151537000_14.4.e013384.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.01.007"},{"key":"2026040909151537000_14.4.e013384.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.03.003"},{"key":"2026040909151537000_14.4.e013384.7","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-332125"},{"key":"2026040909151537000_14.4.e013384.8","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhepr.2024.101130","article-title":"Immunotherapy for hepatocellular carcinoma","volume":"6","author":"Childs","year":"2024","journal-title":"JHEP Rep"},{"key":"2026040909151537000_14.4.e013384.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915745"},{"key":"2026040909151537000_14.4.e013384.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2023.101567"},{"key":"2026040909151537000_14.4.e013384.11","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.13892"},{"key":"2026040909151537000_14.4.e013384.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01868-2"},{"key":"2026040909151537000_14.4.e013384.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.01.011"},{"key":"2026040909151537000_14.4.e013384.14","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-332837"},{"key":"2026040909151537000_14.4.e013384.15","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.jhep.2023.11.030","article-title":"Battle of the biopsies: Role of tissue and liquid biopsy in hepatocellular carcinoma","volume":"80","author":"Lehrich","year":"2024","journal-title":"J Hepatol"},{"key":"2026040909151537000_14.4.e013384.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00816-4"},{"key":"2026040909151537000_14.4.e013384.17","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-331956"},{"key":"2026040909151537000_14.4.e013384.18","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-2566"},{"key":"2026040909151537000_14.4.e013384.19","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1016\/j.annonc.2021.08.1748","article-title":"Plasma proteomics identifies leukemia inhibitory factor (LIF) as a novel predictive biomarker of immune-checkpoint blockade resistance","volume":"32","author":"Loriot","year":"2021","journal-title":"Ann Oncol"},{"key":"2026040909151537000_14.4.e013384.20","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djae079"},{"key":"2026040909151537000_14.4.e013384.21","doi-asserted-by":"crossref","first-page":"360","DOI":"10.3350\/cmh.2024.0042","article-title":"Multiomics profiling of buffy coat and plasma unveils etiology-specific signatures in hepatocellular carcinoma","volume":"30","author":"Hong","year":"2024","journal-title":"Clin Mol Hepatol"},{"key":"2026040909151537000_14.4.e013384.22","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhepr.2022.100648","article-title":"Development and validation of circulating protein signatures as diagnostic biomarkers for biliary tract cancer","volume":"5","author":"Christensen","year":"2023","journal-title":"JHEP Rep"},{"key":"2026040909151537000_14.4.e013384.23","doi-asserted-by":"crossref","DOI":"10.3390\/cancers14040883","article-title":"Interleukin-6 Is a Circulating Prognostic Biomarker for Hepatocellular Carcinoma Patients Treated with Combined Immunotherapy","volume":"14","author":"Myojin","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2026040909151537000_14.4.e013384.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.09.026"},{"key":"2026040909151537000_14.4.e013384.25","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/92.3.205"},{"key":"2026040909151537000_14.4.e013384.26","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1021\/jm300529u","article-title":"Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts","volume":"55","author":"Gieling","year":"2012","journal-title":"J Med Chem"},{"key":"2026040909151537000_14.4.e013384.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.09.035"},{"key":"2026040909151537000_14.4.e013384.28","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhepr.2023.100672","article-title":"High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma","volume":"5","author":"Yang","year":"2023","journal-title":"JHEP Rep"},{"key":"2026040909151537000_14.4.e013384.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0860-1"},{"key":"2026040909151537000_14.4.e013384.30","doi-asserted-by":"crossref","DOI":"10.3390\/cancers16091737","article-title":"High Serum Levels of CCL20 Are Associated with Recurrence and Unfavorable Overall Survival in Advanced Melanoma Patients Receiving Immunotherapy","volume":"16","author":"K\u00f6tt","year":"2024","journal-title":"Cancers (Basel)"},{"key":"2026040909151537000_14.4.e013384.31","doi-asserted-by":"crossref","first-page":"107447","DOI":"10.1016\/j.lungcan.2023.107447","article-title":"Colony stimulating factor-1 (CSF-1) signalling is predictive of response to immune checkpoint inhibitors in advanced non-small cell lung cancer","volume":"188","author":"Takam Kamga","year":"2024","journal-title":"Lung Cancer (Auckl)"},{"key":"2026040909151537000_14.4.e013384.32","doi-asserted-by":"crossref","DOI":"10.1016\/j.xcrm.2022.100901","article-title":"Illuminating the mechanism of IL-6-mediated immunotherapy resistance","volume":"4","author":"Vilgelm","year":"2023","journal-title":"Cell Rep Med"},{"key":"2026040909151537000_14.4.e013384.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0856-x"},{"key":"2026040909151537000_14.4.e013384.34","doi-asserted-by":"crossref","first-page":"101512","DOI":"10.1016\/j.smim.2021.101512","article-title":"Immunomodulatory effects of G-CSF in cancer: Therapeutic implications","volume":"54","author":"Mouchemore","year":"2021","journal-title":"Semin Immunol"},{"key":"2026040909151537000_14.4.e013384.35","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.semcancer.2022.01.001","article-title":"Carbonic anhydrase IX: A tumor acidification switch in heterogeneity and chemokine regulation","volume":"86","author":"Queen","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"2026040909151537000_14.4.e013384.36","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.3892\/ijo.2017.4098","article-title":"Expression of carbonic anhydrase IX is associated with poor prognosis through regulation of the epithelial\u2011mesenchymal transition in hepatocellular carcinoma","volume":"51","author":"Hyuga","year":"2017","journal-title":"Int J Oncol"},{"key":"2026040909151537000_14.4.e013384.37","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-019-09799-0"},{"key":"2026040909151537000_14.4.e013384.38","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0200855","article-title":"Circulating hypoxia marker carbonic anhydrase IX (CA9) in patients with hepatocellular carcinoma and patients with cirrhosis","volume":"13","author":"Finkelmeier","year":"2018","journal-title":"PLoS ONE"},{"key":"2026040909151537000_14.4.e013384.39","first-page":"5447","article-title":"Prognostic value of serum CA9 in patients with metastatic clear cell renal cell carcinoma under targeted therapy","volume":"32","author":"Gigante","year":"2012","journal-title":"Anticancer Res"},{"key":"2026040909151537000_14.4.e013384.40","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/ijc.32163","article-title":"Evaluation of soluble carbonic anhydrase IX as predictive marker for efficacy of bevacizumab: A biomarker analysis from the geparquinto phase III neoadjuvant breast cancer trial","volume":"145","author":"Janning","year":"2019","journal-title":"Int J Cancer"},{"key":"2026040909151537000_14.4.e013384.41","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-1877"},{"key":"2026040909151537000_14.4.e013384.42","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2021.832315","article-title":"CA9-Related Acidic Microenvironment Mediates CD8+ T Cell Related Immunosuppression in Pancreatic Cancer","volume":"11","author":"Yin","year":"2021","journal-title":"Front Oncol"},{"key":"2026040909151537000_14.4.e013384.43","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0657"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2025-013384","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:15:29Z","timestamp":1775751329000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2025-013384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,9]]},"published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1136\/jitc-2025-013384"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2025-013384","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]}}}