Brain metastases exhibit distinct spatial patterns of resident and infiltrating macrophages.

Brain metastases (BrM) are a leading cause of morbidity and mortality, arising in multiple brain compartments. BrM colonization and progression are shaped by interactions with distinct tumor-associated macrophage (TAM) subsets, including microglia (MG), monocyte-derived macrophages (MDM), and border-associated macrophages (BAM). While transcriptomes of TAM have been characterized in detail, their spatial distribution, abundance, and compartment-specific composition -particularly in relation to BrM size and the cancer origin-remain poorly defined. Here, we performed a comprehensive spatial analysis of TAM subtypes across brain regions using experimental BrM models of lung and breast cancer, as well as melanoma. We distinguished TAM subsets by both origin and location, employing genetically traceable mouse models. We observed expansion of MG and BAM, as well as MDM infiltration associated with BrM, albeit with distinct compositions. Parenchymal BrM contained both MG and MDM, whereas ventricular and leptomeningeal BrM contained BAM and MDM but lacked MG. TAM abundance varied with BrM size, compartment, and cancer type: MG predominated in early parenchymal lesions, with MDM becoming dominant as tumors grew. Notably, melanoma BrM exhibited markedly reduced MDM infiltration compared with lung and breast cancer BrM. These findings highlight the need to tailor TAM-targeted therapies not only to the primary tumor type but also to the brain compartment affected. A deeper understanding of TAM dynamics across compartments may improve the precision and efficacy of BrM treatments.