Brain metastases (BrMs) remain a major clinical and therapeutic challenge in patients with metastatic cancers. However, advances in our understanding of BrM have been hampered by the constrained sample size and resolution of BrM profiling studies. Here, we perform integrative single-cell RNA sequencing analysis on 108 BrM samples and 111 primary tumor (PTs) samples to investigate the characteristics and remodeling of cell states and composition across cancer lineages and subsets. Recurring and enriched features of malignant cells are increased chromosomal instability, marked proliferative and angiogenic hallmarks, and adoption of a neural-like BrM-associated metaprogram. Immunosuppressive myeloid and stromal subsets dominate the BrM tumor microenvironment, which are associated with poor prognosis and resistance to immunotherapy. Furthermore, five distinct BrM ecotypes are identified, correlating with specific histopathological patterns and clinical characteristics. This work defines hallmarks of BrM biology across cancer types and suggests that shared dependencies may exist, which may be exploited clinically.Copyright © 2025 Elsevier Inc. All rights reserved.