{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:02:36Z","timestamp":1759190556582,"version":"3.44.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background &amp;amp; Aims<\/jats:title><jats:p>The survival benefit of adding transarterial chemoembolization (TACE) to systemic therapy (tislelizumab plus tyrosine kinase inhibitors [TKIs]) for unresectable hepatocellular carcinoma (HCC) requires validation. This retrospective study compared the efficacy and safety of tislelizumab-TKIs with or without TACE and identified clinical predictors of benefit.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This retrospective analysis included 283 unresectable HCC patients: systemic therapy alone (STG, n=98; tislelizumab plus TKIs) versus combination therapy (CTG, n=185; tislelizumab plus TKIs and TACE). Primary endpoints were overall survival (OS) and progression-free survival (PFS), analyzed by Cox regression. Propensity score matching (PSM) was used to reduce baseline differences between the two groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After PSM, CTG significantly improved median OS (22.5 [95% confidence interval (CI): 19.0\u201334.4] <jats:italic>vs<\/jats:italic>. 14.0 [12.1\u201318.6] months; hazard ratio (HR) 0.53, p&amp;lt;0.001) and PFS (14.6 [12.1\u201319.1] <jats:italic>vs<\/jats:italic>. 9.5 [7.8\u201312.5] months; HR 0.59, p&amp;lt;0.001) versus STG. Multivariate analysis identified independent predictors of poor OS: age &amp;lt;60 years, extrahepatic spread, portal vein thrombus, alpha-fetoprotein (AFP) \u2265400 ng\/mL, and elevated gamma-glutamyl transferase (GGT). Subgroups with maximal CTG benefit included patients aged \u226560 years, no extrahepatic spread, AFP &amp;lt;400 ng\/mL, and normal GGT. CTG had higher all-grade adverse events (79.6% <jats:italic>vs<\/jats:italic>. 67.0%, p=0.021) and grade \u22653 events (23.5% <jats:italic>vs<\/jats:italic>. 14.1%, p=0.038), primarily manageable liver toxicity and hematological abnormalities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Combining TACE with tislelizumab-TKIs significantly improves survival over systemic therapy alone in unresectable HCC, with maximal benefit observed in patients aged \u226560 years, without extrahepatic spread, with AFP &amp;lt;400 ng\/mL, or normal GGT, despite increased manageable toxicity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1664519","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T04:14:09Z","timestamp":1759119249000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tislelizumab plus tyrosine kinase inhibitors with TACE improves survival in unresectable hepatocellular carcinoma with clinical predictors and manageable safety"],"prefix":"10.3389","volume":"16","author":[{"given":"Fengliang","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenxue","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunpeng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qun","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuai","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jncc.2024.01.006","article-title":"Cancer incidence and mortality in China, 2022","volume":"4","author":"Han","year":"2024","journal-title":"J Natl Cancer Cent"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01200-4","article-title":"Hepatocellular carcinoma","volume":"400","author":"Vogel","year":"2022","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007366","article-title":"Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial","volume":"11","author":"Zhang","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2022.7989","article-title":"Management of hepatocellular carcinoma: A review","volume":"158","author":"Brown","year":"2023","journal-title":"JAMA Surg"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.02745","article-title":"Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline update","volume":"42","author":"Gordan","year":"2024","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000528979","article-title":"Prioritized requirements for first-line systemic therapy for hepatocellular carcinoma: broad benefit with less toxicity","volume":"12","author":"Kudo","year":"2023","journal-title":"Liver Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00961-3","article-title":"Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study","volume":"402","author":"Qin","year":"2023","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1001\/jamaoncol.2023.2677","article-title":"Critical appraisal of guideline recommendations on systemic therapies for advanced hepatocellular carcinoma: A review","volume":"10","author":"Cappuyns","year":"2024","journal-title":"JAMA Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1159\/000502479","article-title":"Treatment of intermediate-stage hepatocellular carcinoma in Japan: position of curative therapies","volume":"9","author":"Kariyama","year":"2020","journal-title":"Liver Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105436","article-title":"Gelation embolism agents suppress clinical TACE-incited pro-metastatic microenvironment against hepatocellular carcinoma progression","volume":"109","author":"Song","year":"2024","journal-title":"EBioMedicine"},{"key":"B12","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1038\/s41392-024-02012-x","article-title":"Comparison of drug-eluting bead transarterial chemoembolization combined with apatinib versus drug-eluting bead transarterial chemoembolization for the treatment of unresectable hepatocellular carcinoma: a randomized, prospective, multicenter phase III trial","volume":"9","author":"Duan","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.09.023","article-title":"Role of locoregional therapies in the wake of systemic therapy","volume":"72","author":"Palmer","year":"2020","journal-title":"J Hepatol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41392-022-01235-0","article-title":"Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001)","volume":"8","author":"Zhu","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00392","article-title":"Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: A phase III, randomized clinical trial (LAUNCH)","volume":"41","author":"Peng","year":"2023","journal-title":"J Clin Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2024.108634","article-title":"Efficacy and safety of transarterial chemoembolization combined with lenvatinib and PD-1 inhibitor in the treatment of advanced hepatocellular carcinoma: A meta-analysis","volume":"257","author":"Wang","year":"2024","journal-title":"Pharmacol Ther"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.2147\/ITT.S452339","article-title":"Efficacy of lenvatinib combined with PD-1 inhibitor versus sorafenib and PD-1 inhibitor with or without TACE for hepatocellular carcinoma with extrahepatic metastasis","volume":"13","author":"Duan","year":"2024","journal-title":"Immunotargets Ther"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1109771","article-title":"Prediction of early treatment response to the combination therapy of TACE plus lenvatinib and anti-PD-1 antibody immunotherapy for unresectable hepatocellular carcinoma: Multicenter retrospective study","volume":"14","author":"Li","year":"2023","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1159\/000528356","article-title":"Outcomes of salvage surgery for initially unresectable hepatocellular carcinoma converted by transcatheter arterial chemoembolization combined with lenvatinib plus anti-PD-1 antibodies: A multicenter retrospective study","volume":"12","author":"Wu","year":"2023","journal-title":"Liver Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1430571","article-title":"TACE plus lenvatinib and tislelizumab for intermediate-stage hepatocellular carcinoma beyond up-to-11 criteria: a multicenter cohort study","volume":"15","author":"Chen","year":"2024","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2024.102622","article-title":"Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody\/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study","volume":"72","author":"Jin","year":"2024","journal-title":"EClinicalMedicine"},{"key":"B22","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1055\/s-0030-1247132","article-title":"(mRECIST) assessment for hepatocellular carcinoma","volume":"30","author":"Lencioni","year":"2010","journal-title":"Semin Liver Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.cn112137-20230630-01114","article-title":"Chinese clinical practice guidelines for transarterial chemoembolization of hepatocellular carcinoma (2023 edition)","volume":"103","year":"2023","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N Engl J Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00252-7","article-title":"Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2\u20133 study","volume":"22","author":"Ren","year":"2021","journal-title":"Lancet Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(23)00469-2","article-title":"Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial","volume":"24","author":"Llovet","year":"2023","journal-title":"Lancet Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.11.030","article-title":"Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma","volume":"76","author":"Cheng","year":"2022","journal-title":"J Hepatol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(24)00247-4","article-title":"Combination locoregional and systemic therapies in hepatocellular carcinoma","volume":"10","author":"Zhong","year":"2025","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41575-020-00395-0","article-title":"Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma","volume":"18","author":"Llovet","year":"2021","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1186\/s12943-024-02101-z","article-title":"Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma","volume":"23","author":"Chan","year":"2024","journal-title":"Mol Cancer"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1188308","article-title":"Safety and efficacy of transarterial chemoembolization combined with tyrosine kinase inhibitors and camrelizumab in the treatment of patients with advanced unresectable hepatocellular carcinoma","volume":"14","author":"Li","year":"2023","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.08.028","article-title":"EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma","volume":"82","year":"2025","journal-title":"J Hepatol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1664519\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T04:14:10Z","timestamp":1759119250000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1664519\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":32,"alternative-id":["10.3389\/fimmu.2025.1664519"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1664519","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]},"article-number":"1664519"}}