Mechanisms, Imaging Phenotypes, and Therapeutic Advances of Neovascularization in Brain Metastases

Brain metastases have a distinctive vascular ecosystem-shaped by sprouting angiogenesis, vessel co-option, vasculogenic mimicry, and tumor cell transdifferentiation-that governs tumor perfusion, drug exposure, and therapeutic responsiveness. These heterogeneous vascularization patterns exhibit characteristic differences in enhancement morphology, perfusion levels, and metabolic uptake on contrast-enhanced MRI, perfusion imaging, and amino acid PET, providing crucial imaging cues for identifying routes of blood supply, inferring the state of the blood-tumor barrier, and guiding individualized therapeutic strategies. Anti-VEGF therapy is primarily used to alleviate cerebral edema and radiation necrosis, yet it confers limited survival benefit, underscoring the spatiotemporal heterogeneity of the blood-tumor barrier and the persistence of non-classical vascularization pathways. Building on the concept of "vascular normalization," combinations of anti-angiogenic therapy with immunotherapy, radiotherapy, or targeted agents have shown encouraging intracranial activity in selected settings-most robustly in melanoma brain metastases-but remain insufficiently validated in randomized, brain-metastasis-focused trials. By integrating mechanistic, imaging, and therapeutic perspectives, this review outlines how vascular-ecosystem-based stratification and physics-informed drug-delivery strategies may help transition anti-vascular therapy from symptomatic control toward mechanism-driven precision intervention.