Brain metastasis is the most common type of brain cancer, associated with significant neurological dysfunction and a poor prognosis. We investigated the transcriptome of 128,421 single-cells of 36 brain metastases, originating from a variety of primary tumors, including melanoma, breast, lung, ovarian, colorectal, and renal cancers. Our aim was to identify common molecular factors across these tumors, shedding light on key interactions that facilitate tumor establishment in the brain. We specifically focused on the dynamics of the blood-tumor barrier and its effects on endothelial cells, pericytes, and astrocytes. Our analysis decoded complex cell-cell communications, emphasizing the crucial role of astrocytes in the tumor microenvironment (TME). This provided insights into how these interactions impact the permeability of the blood-tumor barrier and contribute to the development of brain metastases. We identified the VEGFA, SEMA3, and SPP1 pathways as key regulators in brain metastasis, affecting vascular permeability and cellular dynamics. Spatial transcriptome analysis confirmed our findings and linked these pathways to TME enrichment. The pronounced expression of VEGFA by cancer cells suggests a significant activation of angiogenic pathways, influencing vascular responses and the intricate architecture of brain tissue. The interplay of these signaling pathways underlines the complexity of molecular interactions that define the microenvironment of brain metastases.