Metabolic Reprogramming in Brain Metastases: Integrating Spatial Omics with Non-Spatial Mechanistic Evidence

Abstract

Brain metastases (BrMs) develop within a metabolically specialized environment, where nutrient availability and interactions with neural, vascular and immune cells can influence tumor growth. Bulk and single-cell studies have identified metabolic alterations, while spatial approaches provide additional information on their regional and cellular context. This mini review examines spatial transcriptomics, proteomics and mass spectrometry imaging alongside biochemical measurements and functional studies, focusing on central carbon metabolism, glutamate-glutamine metabolism, lipid handling and oxidative phosphorylation. Available spatial studies describe regional differences in metabolism-associated molecular programs, lipid abundance and isotope labeling. Complementary experiments implicate tumor-cell synthesis, host-derived substrate supply and mitochondrial activity in supporting growth in the BrM models. These findings suggest recurring metabolic functions across tumor origins, although whether these functions depend on the same molecular pathways remains uncertain. Some BrM-associated features are also detectable in primary tumors, suggesting that these states may precede brain colonization. We therefore discuss how matched-site comparisons, tracing and cell-specific perturbation could help distinguish pre-existing features from local adaptations and clarify metabolic sources and requirements. Linking tissue findings to longitudinal imaging and liquid-biopsy measurements could support the evaluation of candidate targets and biomarkers while addressing limited opportunities for repeated tissue sampling.