Targeted metabolomics of pancancer brain metastasis

The molecular heterogeneity of brain metastases hampers therapeutic development for cures. To address this unmet and urgent need, we constructed a comprehensive multi-omic, single cell, and spatially resolved atlas of 1,032 pan-cancer brain metastases, identifying four robust molecular subtypes with distinct biological programs and clinical associations. These brain metastases subtypes (BrMS) are defined by unique biological states: neural-like (BrMS1), metabolic (BrMS3), highly proliferative/immune-excluded (BrMS4), and an immune-infiltrated (BrMS2) state featuring a coordinated epithelial-mesenchymal transition program. Patient-derived organoids coupled with targeted drug screening indicate subtype-specific molecular dependencies and putative targets, notably mTOR signaling activation in BrMS3 and CDK4/6 axis activation in BrMS4, while BrMS1 and BrMS2 display distinct radiobiologic and immunologic signatures. This atlas provides a rigorous classification framework of BrMs and offers insights into subtype-specific molecular vulnerabilities.