{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T02:29:04Z","timestamp":1794536944590,"version":"4.9.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"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<\/jats:title><jats:p>The prognosis of metastatic or recurrent hepatocellular carcinoma (HCC) remains poor, and new treatment strategies are warranted. Despite promising preclinical results demonstrating that radiation primes the immune system and produces a synergistic antitumor response for long-term disease control, limited clinical data are available. Therefore, in this study, we investigated the efficacy and safety of combining radiotherapy with immune checkpoint inhibitors (ICIs) for patients with metastatic and recurrent HCC in a real-world setting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Patients with stage IV or recurrent HCC who received sequential or concurrent radiotherapy and ICIs in our institution were enrolled in this study. Data regarding clinicopathological characteristics, treatment protocols, response rates, toxicities, and survival were collected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>From January 2018 to December 2021, 108 patients were included. Extra-hepatic metastasis and portal vein tumor thrombosis were recorded in 58 (53.7%) and 69 patients (63.9%), respectively. A median radiation dose of 55 Gy was administered, and ICIs were administered for 3 weeks until disease progression or limiting toxicities occurred. After treatment, the overall response rate was 75.0%, and the median follow-up duration was 18.8 months. Median overall survival and progression-free survival were 17.0 and 12.6 months, respectively. Only one patient experienced in-field recurrence. Grade \u22653 adverse events were observed in 30.6% of patients. Dermatitis was the most common toxicity-related event and thrombocytopenia was the most common grade \u22653 adverse event, occurring overall in 17.6% of patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The ICI and radiotherapy combination was effective and well-tolerated in real-world patients, achieving more favorable results compared with historical ones and providing a new multimodality therapy for patients with recurrent and metastatic HCC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1594577","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T06:16:06Z","timestamp":1754288166000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Combined radiation and immune checkpoint inhibitor therapy for metastatic or recurrent hepatocellular carcinoma: a real-world study of 108 patients"],"prefix":"10.3389","volume":"16","author":[{"given":"Yirui","family":"Zhai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yefan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxia","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongkun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Lian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningning","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongwen","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye-Xiong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial","volume":"391","author":"Kudo","year":"2018","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S1470-2045(08)70285-7","article-title":"Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial","volume":"10","author":"Cheng","year":"2009","journal-title":"Lancet Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.12.015","article-title":"Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial","volume":"16","author":"Faivre-Finn","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.01055","article-title":"Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133)","volume":"39","author":"Liu","year":"2021","journal-title":"J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.72.1167","article-title":"Pooled analysis safety profile of nivolumab and ipilimumab combination therapy in patients with advanced melanoma","volume":"35","author":"Sznol","year":"2017","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/S1470-2045(21)00604-5","article-title":"Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial","volume":"23","author":"Yau","year":"2022","journal-title":"Lancet Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.00808","article-title":"Phase ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma","volume":"38","author":"Finn","year":"2020","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1200\/JCO.19.01307","article-title":"Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial","volume":"38","author":"Finn","year":"2020","journal-title":"J Clin Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.4564","article-title":"Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the checkMate 040 randomized clinical trial","volume":"6","author":"Yau","year":"2020","journal-title":"JAMA Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/onco.13638","article-title":"The role of immunotherapy in hepatocellular carcinoma: A systematic review and pooled analysis of 2,402 patients","volume":"26","author":"Ziogas","year":"2021","journal-title":"Oncologist"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/00365521.2020.1794539","article-title":"Programmed cell death protein 1 (PD-1)-inhibition in hepatocellular carcinoma (HCC): a single center experience","volume":"55","author":"Mahn","year":"2020","journal-title":"Scand J Gastroenterol"},{"key":"B13","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 2-3 study","volume":"22","author":"Ren","year":"2021","journal-title":"Lancet Oncol"},{"key":"B14","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":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31993","article-title":"Phase 2 study of adjuvant radiotherapy following narrow-margin hepatectomy in patients with HCC","volume":"74","author":"Chen","year":"2021","journal-title":"Hepatology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v27.i20.2434","article-title":"Role of modern radiotherapy in managing patients with hepatocellular carcinoma","volume":"27","author":"Chen","year":"2021","journal-title":"World J Gastroenterol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2022.08.019","article-title":"Systematic review of adjuvant external beam radiotherapy for hepatocellular carcinoma following radical hepatectomy","volume":"175","author":"Wang","year":"2022","journal-title":"Radiother Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2022.109462","article-title":"Survival benefit of radiotherapy following narrow-margin hepatectomy in patients with hepatocellular carcinoma: A propensity score-matched analysis based on phase II study","volume":"180","author":"Long","year":"2023","journal-title":"Radiother Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2020.11.033","article-title":"Stereotactic body radiation therapy for hepatocellular carcinoma with Macrovascular invasion","volume":"156","author":"Munoz-Schuffenegger","year":"2021","journal-title":"Radiother Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17168","article-title":"Radiation improves antitumor effect of immune checkpoint inhibitor in murine hepatocellular carcinoma model","volume":"8","author":"Kim","year":"2017","journal-title":"Oncotarget"},{"key":"B21","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1055\/s-0030-1247132","article-title":"Modified RECIST (mRECIST) assessment for hepatocellular carcinoma","volume":"30","author":"Lencioni","year":"2010","journal-title":"Semin Liver Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/S1470-2045(21)00151-0","article-title":"Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial","volume":"22","author":"Galle","year":"2021","journal-title":"Lancet Oncol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/S0140-6736(16)32453-9","article-title":"Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"389","author":"Bruix","year":"2017","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30011-5","article-title":"Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial","volume":"21","author":"Qin","year":"2020","journal-title":"Lancet Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2991","DOI":"10.1200\/JCO.20.03555","article-title":"Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I\/II study","volume":"39","author":"Kelley","year":"2021","journal-title":"J Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30937-9","article-title":"Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"20","author":"Zhu","year":"2019","journal-title":"Lancet Oncol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1056\/NEJMoa1717002","article-title":"Cabozantinib in patients with advanced and progressing hepatocellular carcinoma","volume":"379","author":"Abou-Alfa","year":"2018","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30351-6","article-title":"Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial","volume":"19","author":"Zhu","year":"2018","journal-title":"Lancet Oncol"},{"key":"B29","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":"B30","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.15411","article-title":"Treatment of hepatocellular carcinoma with portal vein tumor thrombus: advances and challenges","volume":"8","author":"Jiang","year":"2017","journal-title":"Oncotarget"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000003015","article-title":"Multimodality treatment for hepatocellular carcinoma with portal vein tumor thrombus: A large-scale, multicenter, propensity mathching score analysis","volume":"95","author":"Wang","year":"2016","journal-title":"Med (Baltimore)"},{"key":"B32","doi-asserted-by":"publisher","first-page":"4073","DOI":"10.1200\/JCO.2021.39.15_suppl.4073","article-title":"IMbrave150: Exploratory efficacy and safety results of hepatocellular carcinoma (HCC) patients (pts) with main trunk and\/or contralateral portal vein invasion (Vp4) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in a global Ph III study","author":"Breder","year":"2021","journal-title":"ASCO GI"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.7314\/apjcp.2013.14.12.7251","article-title":"Attributable causes of liver cancer mortality and incidence in China","volume":"14","author":"Fan","year":"2013","journal-title":"Asian Pac J Cancer Prev"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-021-02911-w","article-title":"Comparison of HBV reactivation between patients with high HBV-DNA and low HBV-DNA loads undergoing PD-1 inhibitor and concurrent antiviral prophylaxis","volume":"70","author":"He","year":"2021","journal-title":"Cancer Immunol Immunother"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1177\/17588359211002720","article-title":"Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma","volume":"13","author":"He","year":"2021","journal-title":"Ther Adv Med Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00620","article-title":"Pembrolizumab versus placebo as second-line therapy in patients from asia with advanced hepatocellular carcinoma: A randomized, double-blind, phase III trial","volume":"41","author":"Qin","year":"2023","journal-title":"J Clin Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25397","article-title":"PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients","volume":"128","author":"Shi","year":"2011","journal-title":"Int J Cancer"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316510","article-title":"Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma","volume":"68","author":"Lim","year":"2019","journal-title":"Gut"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2024.102422","article-title":"Efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy in potentially resectable stage IIIA\/IIIB non-small cell lung cancer: Neo-Pre-IC, a single-arm phase 2 trial","volume":"68","author":"Sun","year":"2024","journal-title":"EClinicalMedicine"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.clcc.2016.11.003","article-title":"Gastrointestinal perforation and fistula formation in 5 patients with colorectal cancer during treatment with regorafenib","author":"Doi","year":"2016","journal-title":"Clin Colorectal Cancer"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2024.5403","article-title":"Stereotactic body radiotherapy vs sorafenib alone in hepatocellular carcinoma: the NRG oncology\/RTOG 1112 phase 3 randomized clinical trial","volume":"11","author":"Dawson","year":"2025","journal-title":"JAMA Oncol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2024.101287","article-title":"Phase II study with sorafenib plus radiotherapy for advanced HCC with portal and\/or hepatic vein tumor thrombosis","volume":"7","author":"Zhai","year":"2025","journal-title":"JHEP Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2018.6","article-title":"Using immunotherapy to boost the abscopal effect","volume":"18","author":"Ngwa","year":"2018","journal-title":"Nat Rev Cancer"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1594577\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T06:16:07Z","timestamp":1754288167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1594577\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,4]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2025.1594577"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1594577","relation":{"has-part":[{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2025.1594577.s001","asserted-by":"subject"},{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2025.1594577.s002","asserted-by":"subject"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,4]]},"article-number":"1594577"}}