Nature Cancer, Published online: 30 March 2026; doi:10.1038/s43018-026-01139-wCerebrospinal fluid (CSF)-derived cell-free DNA holds promise for CNS tumors, but its limited yield poses challenges. A study now presents M-PACT, a framework that uses sub-nanogram CSF-derived cell-free DNA methylomes for tumor classification, paving the way for minimally invasive diagnosis of pediatric brain tumors.