• Jawad Fares, Edgar Petrosyan, Crismita Dmello, Rimas V Lukas, Roger Stupp, and Maciej S Lesniak.
• Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
• Lancet Oncol. 2025 Feb 1; 26 (2): e111e121e111-e121.

AbstractAdvances in molecular biology, genetics, and epigenetics have refined our understanding of metastatic brain cancer and underscored the need for better classification and targeted approaches. The heterogeneity of brain metastases highlights the differences from their primary source of origin and contributes to therapeutic resistance. Before colonising the brain, tumour cells acquire specialised proficiencies that enable them to capitalise on the unique microenvironment of the brain. The tumour cells further orchestrate key adaptations to adjust to the brain microenvironment by manipulating the blood-brain barrier, evading immune surveillance, rewiring metabolic profiles, and reprogramming astrocytes. These adaptations facilitate tumour survival, growth, and treatment resistance. Recognising metastatic brain cancer as a distinctive CNS disease, rather than an extension of the primary cancer, would support the development of rational approaches that target its molecular and genetic features and improve research funding in this area. Here, we delve into the distinct genetic and phenotypic characteristics of metastatic brain cancer, and reflect on how a change in the perception of this disease could accelerate the development of more effective therapies and drive continued progress in the field of neuro-oncology.Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

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