Immune escape in portal vein tumor thrombus: an intravascular tumor-immune niche framework for hepatocellular carcinoma.

Portal vein tumor thrombus (PVTT) is a major manifestation of macrovascular invasion in hepatocellular carcinoma (HCC) and is associated with aggressive progression and heterogeneous responses to immune checkpoint inhibitor-based therapy. Current stratification relies mainly on anatomical extent, liver function, and tumor burden and does not fully capture the biology of the intravascular lesion. In this Review, we propose PVTT as an anatomically distinct, lesion-centered intravascular tumor-immune niche for hypothesis generation rather than as an established autonomous immune compartment. We distinguish PVTT-direct evidence from supportive venous-thrombus/metastatic evidence and HCC-extrapolated mechanisms. Current PVTT-direct evidence is strongest for clonal and spatial divergence and PVTT-specific stromal remodeling, including myofibroblast-like cancer-associated fibroblast accumulation, NID1-associated immune barriers, and FAP-positive fibroblast/GJA5-positive endothelial hubs. Venous-thrombus studies provide supportive evidence for macrophage-associated immune suppression, including C5aR-positive tumor-associated macrophages, whereas hypoxia-adenosine signaling, adaptive checkpoint activation, and lipid metabolic rewiring remain largely extrapolated candidate mechanisms requiring direct PVTT validation. On this basis, we organize the available evidence into literature-informed candidate resistance phenotypes and outline a translational framework integrating paired primary tumor-PVTT sampling, spatial and single-cell profiling, functional imaging, and liquid biopsy. These phenotypes are conceptual groupings rather than empirically derived or validated patient subtypes and should guide mechanistic testing and biomarker-enriched trial design rather than routine treatment assignment. Prospective PVTT-specific studies with anatomically resolved sampling, longitudinal pharmacodynamic assessment, and biomarker-by-treatment interaction analyses are required to determine whether this lesion-centered niche framework can ultimately provide clinically useful stratification.