Leptomeningeal fibroblasts promote glioblastoma progression by regulating cerebrospinal fluid dynamics

Cerebrospinal fluid (CSF) maintains the homeostasis of central nervous system (CNS) through its unique biochemical composition. Although impaired CSF dynamics is increasingly recognized in glioblastoma (GBM) patients, the mechanistic basis and pathological consequences of GBM-induced CSF defects remain poorly defined. Here, we demonstrate that GBM induces leptomeningeal fibrosis - a previously unrecognized process that disrupts cerebrospinal fluid (CSF) drainage. Mechanistically, this occurs through the activation of NF-κB signaling in leptomeningeal fibroblasts. The resulting signaling cascade triggers pathological activation of fibroblasts, ultimately leading to perivascular fibrosis that physically obstructs CSF drainage pathways. Crucially, compromised CSF clearance creates an immunosuppressive microenvironment that fosters tumor progression. Clinically, leptomeningeal fibrosis in GBM patients correlates with exhausted T cell accumulation. Pharmacological inhibition or conditional P65 (NF-κB subunit) ablation in murine leptomeningeal fibroblasts attenuates fibrosis, enhances T cell infiltration, and restores anti-PD-1 responsiveness in orthotopic GBM models. These findings reveal a critical axis linking CSF dysfunction to GBM immunosuppression, positioning NF-κB/P65 signaling in leptomeningeal fibroblasts as a strategic target to enhance immunotherapy efficacy.