{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T12:37:40Z","timestamp":1786451860964,"version":"build-2736575974"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":73,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100017959","name":"Health Commission of Hebei Province","doi-asserted-by":"crossref","award":["20251285"],"award-info":[{"award-number":["20251285"]}],"id":[{"id":"10.13039\/100017959","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-54949-4","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:46:55Z","timestamp":1780292815000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics integration model of exosome metabolomics and PD-1\/PD-L1 expression for early prediction of immunotherapy efficacy in advanced liver cancer"],"prefix":"10.1038","volume":"16","author":[{"given":"Caixia","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panpan","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"issue":"11","key":"54949_CR1","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1002\/cac2.12345","volume":"42","author":"K Cheng","year":"2022","unstructured":"Cheng, K. et al. Tumor-associated macrophages in liver cancer: From mechanisms to therapy. Cancer Commun. (Lond). 42 (11), 1112\u20131140. https:\/\/doi.org\/10.1002\/cac2.12345 (2022).","journal-title":"Cancer Commun. (Lond)"},{"key":"54949_CR2","doi-asserted-by":"publisher","first-page":"2681","DOI":"10.2147\/JHC.S556306","volume":"12","author":"WL Luo","year":"2025","unstructured":"Luo, W. L. et al. Impact of middle hepatic vein resection during hemihepatectomy on surgical outcomes and long\u2013term prognosis in hepatocellular carcinoma: a retrospective study. J. Hepatocellular Carcinoma. 12, 2681\u20132692. https:\/\/doi.org\/10.2147\/JHC.S556306 (2025).","journal-title":"J. Hepatocellular Carcinoma"},{"key":"54949_CR3","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/978-3-030-65768-0_9","volume":"1311","author":"J Salazar","year":"2021","unstructured":"Salazar, J. & Le, A. The Heterogeneity of Liver Cancer Metabolism. Adv. Exp. Med. Biol. 1311, 127\u2013136. https:\/\/doi.org\/10.1007\/978-3-030-65768-0_9 (2021).","journal-title":"Adv. Exp. Med. Biol."},{"issue":"3","key":"54949_CR4","doi-asserted-by":"publisher","first-page":"178","DOI":"10.5582\/bst.2022.01245","volume":"16","author":"H Maki","year":"2022","unstructured":"Maki, H. & Hasegawa, K. Advances in the surgical treatment of liver cancer. Biosci. Trends. 16 (3), 178\u2013188. https:\/\/doi.org\/10.5582\/bst.2022.01245 (2022).","journal-title":"Biosci. Trends"},{"key":"54949_CR5","doi-asserted-by":"publisher","first-page":"1070961DOI","DOI":"10.3389\/fimmu.2022.1070961","volume":"13","author":"Q Li","year":"2022","unstructured":"Li, Q., Han, J., Yang, Y. & Chen, Y. PD-1\/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy. Front. Immunol. 13, 1070961DOI. https:\/\/doi.org\/10.3389\/fimmu.2022.1070961 (2022).","journal-title":"Front. Immunol."},{"key":"54949_CR6","doi-asserted-by":"publisher","DOI":"10.1159\/000549355","author":"J Li","year":"2025","unstructured":"Li, J. et al. Rechallenge with immune checkpoint inhibitors in patients with hepatocellular carcinoma: a narrative review. Liver Cancer. https:\/\/doi.org\/10.1159\/000549355 (2025).","journal-title":"Liver Cancer"},{"issue":"8048","key":"54949_CR7","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1038\/s41586-024-08305-z","volume":"637","author":"I Melero","year":"2025","unstructured":"Melero, I. et al. Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours. Nature 637 (8048), 1218\u20131227. https:\/\/doi.org\/10.1038\/s41586-024-08305-z (2025).","journal-title":"Nature"},{"issue":"7938","key":"54949_CR8","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41586-022-05400-x","volume":"612","author":"R Xue","year":"2022","unstructured":"Xue, R. et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature 612 (7938), 141\u2013147. https:\/\/doi.org\/10.1038\/s41586-022-05400-x (2022).","journal-title":"Nature"},{"issue":"4","key":"54949_CR9","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.jhep.2023.01.011","volume":"78","author":"Y Liu","year":"2023","unstructured":"Liu, Y. et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J. Hepatol. 78 (4), 770\u2013782. https:\/\/doi.org\/10.1016\/j.jhep.2023.01.011 (2023).","journal-title":"J. Hepatol."},{"key":"54949_CR10","doi-asserted-by":"publisher","unstructured":"Yeo, Y. H. et al. Alpha-fetoprotein: Past, present, and future. Hepatol. Commun. 8 (5). https:\/\/doi.org\/10.1097\/hc9.0000000000000422 (2024).","DOI":"10.1097\/hc9.0000000000000422"},{"issue":"1","key":"54949_CR11","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/s41419-022-04506-4","volume":"13","author":"C Zhang","year":"2022","unstructured":"Zhang, C. et al. Cancer-derived exosomal HSPC111 promotes colorectal cancer liver metastasis by reprogramming lipid metabolism in cancer-associated fibroblasts. Cell. Death Dis. 13 (1), 57. https:\/\/doi.org\/10.1038\/s41419-022-04506-4 (2022).","journal-title":"Cell. Death Dis."},{"issue":"1","key":"54949_CR12","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/s13045-020-00991-2","volume":"13","author":"S Zhao","year":"2020","unstructured":"Zhao, S. et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J. Hematol. Oncol. 13 (1), 156. https:\/\/doi.org\/10.1186\/s13045-020-00991-2 (2020).","journal-title":"J. Hematol. Oncol."},{"issue":"5","key":"54949_CR13","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/j.jhep.2024.01.011","volume":"80","author":"P Tabrizian","year":"2024","unstructured":"Tabrizian, P., Abdelrahim, M. & Schwartz, M. Immunotherapy and transplantation for hepatocellular carcinoma. J. Hepatol. 80 (5), 822\u2013825. https:\/\/doi.org\/10.1016\/j.jhep.2024.01.011 (2024).","journal-title":"J. Hepatol."},{"key":"54949_CR14","doi-asserted-by":"publisher","first-page":"1714314","DOI":"10.3389\/fimmu.2026.1714314","volume":"17","author":"ZX Luo","year":"2026","unstructured":"Luo, Z. X. et al. Prognostic value of lymphatic vessel density in the capsule of early\u2013stage hepatocellular carcinoma: implications for postoperative recurrence risk. Front. Immunol. 17, 1714314. https:\/\/doi.org\/10.3389\/fimmu.2026.1714314 (2026).","journal-title":"Front. Immunol."},{"issue":"5","key":"54949_CR15","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1159\/000530495","volume":"12","author":"J Zhou","year":"2023","unstructured":"Zhou, J. et al. Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition). Liver Cancer. 12 (5), 405\u2013444. https:\/\/doi.org\/10.1159\/000530495 (2023).","journal-title":"Liver Cancer"},{"issue":"1","key":"54949_CR16","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.cld.2024.08.010","volume":"29","author":"E Kinsey","year":"2025","unstructured":"Kinsey, E. & Morse, M. A. Systemic Therapy for Hepatocellular Carcinoma. Clin. Liver Dis. 29 (1), 105\u2013124. https:\/\/doi.org\/10.1016\/j.cld.2024.08.010 (2025).","journal-title":"Clin. Liver Dis."},{"issue":"13","key":"54949_CR17","doi-asserted-by":"publisher","first-page":"13978","DOI":"10.1002\/cam4.6033","volume":"12","author":"F Costa","year":"2023","unstructured":"Costa, F. et al. Systemic treatment in patients with Child-Pugh B liver dysfunction and advanced hepatocellular carcinoma. Cancer Med. 12 (13), 13978\u201313990. https:\/\/doi.org\/10.1002\/cam4.6033 (2023).","journal-title":"Cancer Med."},{"issue":"15","key":"54949_CR18","doi-asserted-by":"publisher","first-page":"1830","DOI":"10.1200\/jco.23.02745","volume":"42","author":"JD Gordan","year":"2024","unstructured":"Gordan, J. D. et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update. J. Clin. Oncol. 42 (15), 1830\u20131850. https:\/\/doi.org\/10.1200\/jco.23.02745 (2024).","journal-title":"J. Clin. Oncol."},{"key":"54949_CR19","doi-asserted-by":"publisher","unstructured":"Lee, P. C. et al. Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. J. Immunother Cancer. 10 (6). https:\/\/doi.org\/10.1136\/jitc-2022-004779 (2022).","DOI":"10.1136\/jitc-2022-004779"},{"issue":"3","key":"54949_CR20","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1007\/s12094-024-03644-9","volume":"27","author":"Y Lu","year":"2025","unstructured":"Lu, Y. & Lu, Y. Clinical predictive factors of the efficacy of immune checkpoint inhibitors and kinase inhibitors in advanced hepatocellular cancer. Clin. Transl Oncol. 27 (3), 1142\u20131154. https:\/\/doi.org\/10.1007\/s12094-024-03644-9 (2025).","journal-title":"Clin. Transl Oncol."},{"key":"54949_CR21","doi-asserted-by":"publisher","first-page":"1215745DOI","DOI":"10.3389\/fimmu.2023.1215745","volume":"14","author":"D Ma","year":"2023","unstructured":"Ma, D. et al. Development and validation of prognostic risk prediction models for hepatocellular carcinoma patients treated with immune checkpoint inhibitors based on a systematic review and meta-analysis of 47 cohorts. Front. Immunol. 14, 1215745DOI. https:\/\/doi.org\/10.3389\/fimmu.2023.1215745 (2023).","journal-title":"Front. Immunol."},{"issue":"4","key":"54949_CR22","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1007\/s12072-025-10806-6","volume":"19","author":"A Rocco","year":"2025","unstructured":"Rocco, A. et al. Systemic inflammatory response markers improve the discrimination for prognostic model in hepatocellular carcinoma. Hepatol. Int. 19 (4), 915\u2013928. https:\/\/doi.org\/10.1007\/s12072-025-10806-6 (2025).","journal-title":"Hepatol. Int."},{"issue":"1","key":"54949_CR23","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1002\/hep.32256","volume":"76","author":"H Kawai","year":"2022","unstructured":"Kawai, H. et al. Sphingosine-1-phosphate promotes tumor development and liver fibrosis in mouse model of congestive hepatopathy. Hepatology 76 (1), 112\u2013125. https:\/\/doi.org\/10.1002\/hep.32256 (2022).","journal-title":"Hepatology"},{"issue":"21","key":"54949_CR24","doi-asserted-by":"publisher","first-page":"eadv0558","DOI":"10.1126\/sciadv.adv0558","volume":"11","author":"X Zhang","year":"2025","unstructured":"Zhang, X. et al. Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma. Sci. Adv. 11 (21), eadv0558. https:\/\/doi.org\/10.1126\/sciadv.adv0558 (2025).","journal-title":"Sci. Adv."},{"issue":"43","key":"54949_CR25","doi-asserted-by":"publisher","first-page":"eado9311","DOI":"10.1126\/sciadv.ado9311","volume":"10","author":"X Shi","year":"2024","unstructured":"Shi, X. et al. Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice. Sci. Adv. 10 (43), eado9311. https:\/\/doi.org\/10.1126\/sciadv.ado9311 (2024).","journal-title":"Sci. Adv."},{"issue":"9","key":"54949_CR26","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1038\/s41419-022-05210-z","volume":"13","author":"X Wang","year":"2022","unstructured":"Wang, X. et al. S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression. Cell. Death Dis. 13 (9), 768. https:\/\/doi.org\/10.1038\/s41419-022-05210-z (2022).","journal-title":"Cell. Death Dis."},{"key":"54949_CR27","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.70047","author":"Y Zhan","year":"2025","unstructured":"Zhan, Y. et al. Targeting SPHK1 in macrophages remodels the tumor microenvironment and enhances anti-PD-1 immunotherapy efficacy in colorectal cancer liver metastasis. Cancer Commun. (Lond). https:\/\/doi.org\/10.1002\/cac2.70047 (2025).","journal-title":"Cancer Commun. (Lond)"},{"issue":"1","key":"54949_CR28","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s12967-023-04830-z","volume":"22","author":"XT Liu","year":"2024","unstructured":"Liu, X. T. et al. Targeting the SphK1\/S1P\/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis. J. Transl Med. 22 (1), 43. https:\/\/doi.org\/10.1186\/s12967-023-04830-z (2024).","journal-title":"J. Transl Med."},{"issue":"1","key":"54949_CR29","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1159\/000540804","volume":"106","author":"F Zhang","year":"2025","unstructured":"Zhang, F. et al. NEIL3 Upregulated by TFAP2A Promotes M2 Polarization of Macrophages in Liver Cancer via the Mediation of Glutamine Metabolism. Digestion 106 (1), 30\u201344. https:\/\/doi.org\/10.1159\/000540804 (2025).","journal-title":"Digestion"},{"issue":"1","key":"54949_CR30","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1186\/s12967-025-06694-x","volume":"23","author":"X Ruan","year":"2025","unstructured":"Ruan, X. et al. Proteomic and metabolomic analysis of platelet related samples reveals energy metabolism disorders in hepatocellular carcinoma. J. Transl Med. 23 (1), 654. https:\/\/doi.org\/10.1186\/s12967-025-06694-x (2025).","journal-title":"J. Transl Med."},{"issue":"2","key":"54949_CR31","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1053\/j.gastro.2024.02.025","volume":"167","author":"J Chen","year":"2024","unstructured":"Chen, J. et al. TGF-\u03b21-Induced SOX18 Elevation Promotes Hepatocellular Carcinoma Progression and Metastasis Through Transcriptionally Upregulating PD-L1 and CXCL12. Gastroenterology 167 (2), 264\u2013280. https:\/\/doi.org\/10.1053\/j.gastro.2024.02.025 (2024).","journal-title":"Gastroenterology"},{"issue":"1","key":"54949_CR32","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.jhep.2023.02.032","volume":"79","author":"J Tan","year":"2023","unstructured":"Tan, J. et al. TREM2(+) macrophages suppress CD8(+) T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma. J. Hepatol. 79 (1), 126\u2013140. https:\/\/doi.org\/10.1016\/j.jhep.2023.02.032 (2023).","journal-title":"J. Hepatol."},{"key":"54949_CR33","doi-asserted-by":"publisher","first-page":"102463DOI","DOI":"10.1016\/j.redox.2022.102463","volume":"56","author":"X Hao","year":"2022","unstructured":"Hao, X. et al. Inhibition of APOC1 promotes the transformation of M2 into M1 macrophages via the ferroptosis pathway and enhances anti-PD1 immunotherapy in hepatocellular carcinoma based on single-cell RNA sequencing. Redox Biol. 56, 102463DOI. https:\/\/doi.org\/10.1016\/j.redox.2022.102463 (2022).","journal-title":"Redox Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-54949-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-54949-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-54949-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T12:04:20Z","timestamp":1786449860000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-54949-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,30]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["54949"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-54949-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,30]]},"assertion":[{"value":"10 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by the Ethics Committee of Handan First Hospital and was conducted in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"24851"}}