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

## TL;DR

This review explores how brain metastases develop unique blood vessel patterns, how these can be imaged, and how treatments targeting these vessels can be improved for better outcomes.

## Contribution

The paper integrates vascular mechanisms, imaging features, and therapeutic strategies to propose precision interventions for brain metastases.

## Key findings

- Brain metastases exhibit diverse vascularization patterns detectable via MRI, perfusion imaging, and PET.
- Anti-VEGF therapy provides limited survival benefit due to persistent non-classical vascular pathways.
- Combining anti-angiogenic therapy with immunotherapy or radiotherapy shows promise in melanoma brain metastases.

## Abstract

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.