Spatial Immune Remodeling during Neoadjuvant Therapy in Hepatocellular Carcinoma: Mechanisms, Clinical Implications, and Future Perspectives

: Neoadjuvant therapy is an emerging strategy for hepatocellular carcinoma (HCC), particularly in cases with technically resectable but biologically high-risk disease. Neoadjuvant therapy aims to reduce tumor burden and postoperative recurrence risk in high-risk HCC, while also providing a unique opportunity to preoperatively remodel the tumor microenvironment (TME). Recent advances in spatial multiomics have shown that the HCC immune microenvironment is highly heterogeneous, with distinct immune landscapes across the tumor core, invasive front, and adjacent liver tissue. At the spatial level, neoadjuvant therapy may reorganize the HCC tumor microenvironment beyond simple changes in immune-cell abundance. It reshapes the localization and interaction networks of tumor, immune, stromal, and vascular cells, including immune-cell infiltration into tumor nests, tumor–immune cell proximity, vascular accessibility, fibrotic exclusion barriers, and residual resistant niches. Collectively, these spatial changes influence pathological response, microvascular invasion, recurrence risk, and perioperative decision-making. However, key challenges include optimal patient selection, response evaluation, treatment sequencing, surgery timing, and perioperative safety management. Future integration of spatial omics, ctDNA, radiomics, digital pathology, and artificial intelligence may enable further developments in biology-guided neoadjuvant therapy and precise perioperative management of HCC.