Tumor-Associated Macrophages Promote Brain Metastasis

Abstract

Brain metastasis affects 20-40% of cancer patients and remains largely incurable, yet how metastatic cells engage and remodel brain-barrier interfaces is poorly understood. This gap stems in large part from the scarcity of genetically tractable in vivo systems that can resolve tumor-host interactions in their native context. Although tumor-associated macrophages (TAMs) dominate the brain metastatic microenvironment, their causal contribution to colonization has been difficult to establish. Here, we develop the adult Drosophila brain as a platform to address these questions, using allograft transplantation of lgl-/- neural stem cell-derived tumors. We find that tumors colonize the brain surface and deform it through collective, sheet-like invasion, recapitulating features of human leptomeningeal disease without parenchymal infiltration. While tumors compromise both functional and structural integrity of blood-brain barrier, they fail to breach the basement membrane (BM), which we identify as the principal barrier restricting invasion. Critically, tumors recruit TAMs to the metastasized tumor, and genetic depletion of TAMs markedly reduces brain metastasis without affecting initial dissemination. This establishes a causal role for macrophages in brain colonization, potentially through BM remodeling. Together, these findings reveal a conserved, macrophage-dependent mechanism of brain metastasis and provide a genetically accessible model that fills a critical gap in the field.