Vascular-immune zonation sets organ-specific metastatic checkpoints

Organ-specific metastatic niches begin at vascular-immune interfaces, where endothelial heterogeneity and tissue-resident immunity shape the fate of disseminated tumor cells. Hemodynamics and vascular geometry shape initial tumor-cell encounters, whereas endothelial and perivascular immune states determine whether arrest progresses to extravasation, immune elimination, dormancy, or outgrowth. This Mini Review uses vascular-immune zonation as an organizing framework for comparing four common metastatic sites. In the lung, capillary endothelium, alveolar macrophages, and rapidly recruited neutrophils form a responsive barrier that can switch from tumor control to metastatic support. Liver sinusoids couple scavenging and immune tolerance, allowing Kupffer cells and recruited macrophages to exert stage-dependent effects that can also suppress systemic immunotherapy. At the blood-brain barrier, endothelial and mural-cell states interact with microglia and astrocytes to control entry and adaptation. In bone, specialized vessels overlap with hematopoietic and osteogenic niches that metastatic cells exploit for immune evasion and dormancy escape. Across organs, the same immune-cell label does not imply the same function because location, ontogeny, and neighboring stromal cells constrain cell state. Therapeutic design should therefore target pathogenic microdomains and transition states rather than deplete a cell class throughout the body. Spatially matched sampling of metastatic lesions, adjacent tissue, and blood will be needed to translate this site-aware model into biomarkers and combination therapies.