{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:04:55Z","timestamp":1790661895164,"version":"4.1.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"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. Bioeng. Biotechnol."],"abstract":"<jats:p>Thermal ablation is an important local treatment for hepatocellular carcinoma (HCC), yet post-ablation local tumor progression remains a major obstacle to durable disease control. Traditionally, recurrence has been attributed mainly to incomplete thermal coverage, inadequate ablative margins, or heat-sink effects. However, increasing evidence suggests that the sublethal thermal injury (STI) zone at the ablation margin is not merely a passive physical boundary, but a biologically active injury-repair microenvironment. Within this region, gradients of thermal dose, hypoxia, damage-associated molecular patterns (DAMPs), extracellular matrix mechanics, and immune infiltration may interact to shape residual tumor cell behavior. Post-ablation remodeling is likely driven by coordinated crosstalk among myeloid cells, hepatic stellate cells\/cancer-associated fibroblast-like stromal cells (HSCs\/CAFs), endothelial cells, neutrophils, adaptive immune cells, and residual tumor cells. These interactions may promote epithelial\u2013mesenchymal transition, stem-like plasticity, immune evasion, angiogenic repair, and local tumor progression. Current two-dimensional (2D) cultures lack three-dimensional architecture and multicellular spatial interactions, whereas animal models are limited by variable thermal dose control, restricted real-time imaging, and interspecies differences. Emerging HCC organoid-on-a-chip platforms may help address these gaps by integrating patient-derived organoids (PDOs), tunable extracellular matrix hydrogels, microfluidic thermal and hypoxic gradients, and defined multicellular co-culture modules. Importantly, immune checkpoint testing requires immune-competent extensions incorporating autologous T cells, and antigen-presentation studies require dendritic cells. This review discusses the ablation margin as a multicellular recurrence niche and evaluates organoid-on-a-chip systems as hypothesis-generating tools for mechanism-guided and safety-conscious adjuvant strategy development.<\/jats:p>","DOI":"10.3389\/fbioe.2026.1952704","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:46:30Z","timestamp":1790660790000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The ablation margin as a regenerative and immunosuppressive niche in hepatocellular carcinoma: multicellular remodeling and organoid-on-a-chip modeling"],"prefix":"10.3389","volume":"14","author":[{"given":"Tingyue","family":"Qiao","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery, Chongqing Qijiang District People\u2019s Hospital (Jiangsu Provincial People\u2019s Hospital Chongqing Hospital)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zha","sequence":"additional","affiliation":[{"name":"Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghua","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Chongqing Qijiang District People\u2019s Hospital (Jiangsu Provincial People\u2019s Hospital Chongqing Hospital)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Chai","sequence":"additional","affiliation":[{"name":"Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Chongqing Qijiang District People\u2019s Hospital (Jiangsu Provincial People\u2019s Hospital Chongqing Hospital)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1146\/annurev-pathol-052016-100322","article-title":"The role of cancer-associated fibroblasts and fibrosis in liver cancer","volume":"12","author":"Affo","year":"2017","journal-title":"Annu. 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