CSF proteomics using mass spectrometry enables GBM biomarker discovery from small volumes (~30 μL). Mikolajewics et al., identified 755 unique proteins in 73 CSF samples (22 GBM), with MGMT and IDH statuses accurately detected at 94.1% and 33.3%, respectively. Single-cell RNA sequencing confirmed GAP43 as GBM-specific, while TFF3 and CACNA2D2 were specific to BM and CNS lymphoma. Here, CACNA2D2 is linked to primary central nervous system lymphoma.