The ablation margin as a regenerative and immunosuppressive niche in hepatocellular carcinoma: multicellular remodeling and organoid-on-a-chip modeling.

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-mesenchymal 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.