{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:54:07Z","timestamp":1790441647422,"version":"4.1.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"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>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The optimal timing of surgery after conversion therapy for initially unresectable hepatocellular carcinoma (uHCC) remains unclear. This study aimed to evaluate whether surgical timing can be optimized by integrating major pathological response (MPR), defined as residual viable tumor (RVT) \u226415%, with preoperative treatment duration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This multicenter retrospective study enrolled patients with initially uHCC who underwent curative-intent hepatectomy after comprehensive conversion therapy at seven tertiary hospitals between January 2020 and December 2025. The prognostic cutoff for MPR was determined using restricted cubic spline (RCS) models. Patients were categorized into three groups according to the interval from initiation of conversion therapy to surgery: &amp;lt;12 weeks, 12\u201324 weeks, and &amp;gt;24 weeks. MPR rates, survival outcomes, and perioperative safety were compared among the three groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 257 patients were included. RCS analysis showed that a higher RVT proportion was associated with increased risks of poor overall survival (OS) and recurrence-free survival (RFS), with the most pronounced change in risk observed at an RVT threshold of 15%. Therefore, RVT \u226415% was defined as MPR in this study. The overall MPR rate was 63.4% (163\/257). MPR was an independent protective factor for both OS and RFS. The MPR rate increased progressively with longer treatment duration (41.3% in the &amp;lt;12-week group, 66.2% in the 12\u201324-week group, and 73.0% in the &amp;gt;24-week group). OS differed significantly among the three duration groups, whereas the difference in RFS was not statistically significant. The incidences of severe postoperative complications and high-grade adverse events were low across all groups and did not increase markedly with prolonged therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>RVT \u226415% may serve as a prognostically meaningful criterion for MPR after conversion therapy for uHCC. To balance the degree of pathological response, long-term survival benefit, and perioperative safety, a treatment-to-surgery interval of 12 to 24 weeks may be optimal.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1911781","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:35:57Z","timestamp":1789968957000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Optimal timing of surgery after conversion therapy for initially unresectable hepatocellular carcinoma: a multicenter study integrating major pathological response and treatment duration"],"prefix":"10.3389","volume":"17","author":[{"given":"Siming","family":"Li","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Guangxi Medical University Cancer Hospital","place":["Nanning, China"]},{"name":"Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Guilin Medical University","place":["Guilin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Guangxi Medical University Cancer Hospital","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, The First Affiliated Hospital of Guilin Medical University","place":["Guilin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Guangxi Medical University Cancer Hospital","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiling","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Guangxi Medical University Cancer Hospital","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JiaWen","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Guangxi Medical University Cancer Hospital","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Wuming Hospital Affiliated to Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Yulin Red Cross Hospital","place":["Yulin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyin","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Yulin First People\u2019s Hospital","place":["Yulin, Guangxi Zhuang Autonomous Region, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaning","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxia","family":"He","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Second Nanning People\u2019s Hospital","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The First Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Guangxi Medical University Cancer Hospital","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bangde","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Guangxi Medical University Cancer Hospital","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","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"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2025.03.047","article-title":"Advances in locoregional and systemic treatments for hepatocellular carcinoma","volume":"169","author":"Singal","year":"2025","journal-title":"Gastroenterology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/bjsopen\/zrac114","article-title":"Conversion therapy for initially unresectable hepatocellular carcinoma using a combination of toripalimab, lenvatinib plus TACE: real-world study","volume":"6","author":"Qu","year":"2022","journal-title":"BJS Open"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-023-10502-3","article-title":"Efficacy and safety of lenvatinib plus PD-1 inhibitor with or without transarterial chemoembolization in unresectable hepatocellular carcinoma","volume":"17","author":"Xin","year":"2023","journal-title":"Hepatol Int"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000000256","article-title":"TACE-HAIC combined with targeted therapy and immunotherapy versus TACE alone for hepatocellular carcinoma with portal vein tumour thrombus: a propensity score matching study","volume":"109","author":"Yuan","year":"2023","journal-title":"Int J Surg"},{"key":"B7","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1159\/000546052","article-title":"Survival benefit of hepatectomy after complete or partial response to conversion therapy in unresectable hepatocellular carcinoma (GUIDANCE003): a multicenter study","volume":"14","author":"Yang","year":"2025","journal-title":"Liver Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1159\/000514313","article-title":"Downstaging and resection of initially unresectable hepatocellular carcinoma with tyrosine kinase inhibitor and anti-PD-1 antibody combinations","volume":"10","author":"Zhu","year":"2021","journal-title":"Liver Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02660-6","article-title":"Association between pathologic response and survival after neoadjuvant therapy in lung cancer","volume":"30","author":"Deutsch","year":"2024","journal-title":"Nat Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1159\/000541249","article-title":"Consensus of Chinese experts on neoadjuvant and conversion therapies for hepatocellular carcinoma: 2023 update","volume":"14","author":"Bi","year":"2025","journal-title":"Liver Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.67.6049","article-title":"Effect of interval (7 or 11 weeks) between neoadjuvant radiochemotherapy and surgery on complete pathologic response in rectal cancer: a multicenter, randomized, controlled trial (GRECCAR-6)","volume":"34","author":"Lefevre","year":"2016","journal-title":"J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.10.018","article-title":"Updated pan-tumor guidelines for neoadjuvant scoring of pathologic response: a joint SITC and INMC effort","volume":"37","author":"Deutsch","year":"2026","journal-title":"Ann Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1159\/000536376","article-title":"Prognostic value of pathological response for patients with unresectable hepatocellular carcinoma undergoing conversion surgery","volume":"13","author":"Zeng","year":"2024","journal-title":"Liver Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00457-1","article-title":"Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis","volume":"25","author":"D'Alessio","year":"2024","journal-title":"Lancet Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2025.101638","article-title":"Pathological response \u226590% predicts survival in HCC treated with neoadjuvant loco-regional therapies: a retrospective cohort study","volume":"8","author":"Ou-Yang","year":"2026","journal-title":"JHEP Rep"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2024.09.1443","article-title":"Improved event-free survival after complete or major pathologic response in patients with resectable NSCLC treated with neoadjuvant chemoimmunotherapy regardless of adjuvant treatment: a systematic review and individual patient data meta-analysis","volume":"20","author":"Marinelli","year":"2025","journal-title":"J Thorac Oncol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.annonc.2025.02.006","article-title":"Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"36","author":"Vogel","year":"2025","journal-title":"Ann Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(25)00049-4","article-title":"Organ preservation after total neoadjuvant therapy for locally advanced rectal cancer (CAO\/ARO\/AIO-16): an open-label, multicentre, single-arm, phase 2 trial","volume":"10","author":"Gani","year":"2025","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1056\/NEJMoa2415434","article-title":"Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer","volume":"393","author":"Uppaluri","year":"2025","journal-title":"N Engl J Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"498","DOI":"10.3322\/caac.70018","article-title":"Advances in the treatment of hepatocellular carcinoma: an overview of the current and evolving therapeutic landscape for clinicians","volume":"75","author":"Moris","year":"2025","journal-title":"CA Cancer J Clin"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-026-02708-2","article-title":"Sintilimab (PD-1 inhibitor) plus lenvatinib as conversion therapy followed by sequential surgery (SILENSES) for advanced unresectable hepatocellular carcinoma: a phase II, expansion trial","volume":"11","author":"Lu","year":"2026","journal-title":"Signal Transduct Target Ther"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2025.101587","article-title":"Prognostic value of radiological and pathological complete response following immune-based conversion therapy in patients with unresectable hepatocellular carcinoma (GUIDANCE004)","volume":"7","author":"Yang","year":"2025","journal-title":"JHEP Rep"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2024.03.010","article-title":"Evaluation of major pathologic response and pathologic complete response as surrogate end points for survival in randomized controlled trials of neoadjuvant immune checkpoint blockade in resectable in NSCLC","volume":"19","author":"Hines","year":"2024","journal-title":"J Thorac Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.21037\/hbsn-22-527","article-title":"Pathologic assessment of hepatocellular carcinoma in the era of immunotherapy: a narrative review","volume":"13","author":"Wang","year":"2024","journal-title":"Hepatobiliary Surg Nutr"},{"key":"B25","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/s41392-024-01991-1","article-title":"Envafolimab plus lenvatinib and transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: a prospective, single-arm, phase II study","volume":"9","author":"Chen","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03254-6","article-title":"ctDNA-based molecular residual disease and survival in resectable colorectal cancer","volume":"30","author":"Nakamura","year":"2024","journal-title":"Nat Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1038\/s41571-023-00815-5","article-title":"Drug-tolerant persister cells in cancer: the cutting edges and future directions","volume":"20","author":"Pu","year":"2023","journal-title":"Nat Rev Clin Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)02575-3","article-title":"Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study","volume":"405","author":"Kudo","year":"2025","journal-title":"Lancet"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m4087","article-title":"Mortality due to cancer treatment delay: systematic review and meta-analysis","volume":"371","author":"Hanna","year":"2020","journal-title":"BMJ"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-004656","article-title":"Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial","volume":"10","author":"Xia","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1159\/000550954","article-title":"Survival outcomes, recurrence patterns, and its corresponding therapeutic management after conversion therapy followed by curative resection for hepatocellular carcinoma: a real-world study","author":"Xiao","year":"2026","journal-title":"Liver Cancer"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1159\/000549793","article-title":"Pathological complete response after systemic therapy and curative resection in initially unresectable hepatocellular carcinoma: feasibility of a tumor-free with drug-free strategy","author":"Lin","year":"2025","journal-title":"Liver Cancer"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-026-05029-x","article-title":"Adjuvant systemic therapy versus active surveillance after resection following conversion therapy for hepatocellular carcinoma: a propensity score matched study","author":"He","year":"2026","journal-title":"BMC Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.21037\/hbsn-2026-0153","article-title":"Continuous adjuvant therapy with the same regimen improves survival following conversion therapy and hepatectomy in initially unresectable hepatocellular carcinoma: a multicenter retrospective study","author":"Yang","year":"2026","journal-title":"Hepatobiliary Surg Nutr"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1911781\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:35:58Z","timestamp":1789968958000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1911781\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":34,"alternative-id":["10.3389\/fimmu.2026.1911781"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1911781","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]},"article-number":"1911781"}}