Leptomeningeal fibroblasts promote glioblastoma progression by regulating cerebrospinal fluid dynamics

Abstract Cerebrospinal fluid contributes to homeostasis in the central nervous system, but how its dynamics are altered in glioblastoma is unclear. We find that glioblastoma drives leptomeningeal perivascular fibrosis that is associated with impaired fluid transport and clearance. Lineage tracing and single-cell analyses in male tumor-bearing mice identify leptomeningeal fibroblasts as the principal source of this fibrotic response, with limited contribution from pericytes. Fibrosis is linked to activation of nuclear factor kappa B signaling in collagen-producing fibroblasts, extracellular matrix deposition around perivascular spaces, reduced intratumoural cytotoxic T cell accumulation and a less permissive immune microenvironment. Here, we show that inhibiting nuclear factor kappa B signaling in leptomeningeal fibroblasts reduces fibrosis, improves fluid clearance, enhances intratumoural cytotoxic T cell accumulation and restores responsiveness to programmed cell death protein 1 blockade, identifying this pathway as a therapeutic target in glioblastoma.