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.
Authors
- Bin Liu (ORCID: https://orcid.org/0000-0002-5051-8006)
- Houshi Xu (ORCID: https://orcid.org/0000-0002-2878-0913)
- Qisheng Tang (ORCID: https://orcid.org/0000-0003-2954-2797)
- Shan Jiang (ORCID: https://orcid.org/0000-0003-1015-126X)
- Yudan Chi (ORCID: https://orcid.org/0000-0002-4566-3305)
- Maoyuan Sun (ORCID: https://orcid.org/0009-0003-1247-182X)
- Yue Wang (ORCID: https://orcid.org/0000-0003-0802-1140)
- Chong Liu (ORCID: https://orcid.org/0000-0001-6578-5919)
- Zhiyong Qin (ORCID: https://orcid.org/0000-0002-7434-7985)
- Ying Mao (ORCID: https://orcid.org/0000-0001-8055-115X)
- Yulai Zeng
- Ruize Zhu
- Songlin Yan
- Weiqiu Ping
- Yanlin Teng
- Wenli Zhang
- Zhen Fan
- Jiawen Chen
- Zhifeng Shi
- Yun Guan
Institutions
- Chongqing University (CN)
- Shanghai Jiao Tong University (CN)
- Dalian Medical University (CN)
- Fudan University (CN)
- Second Affiliated Hospital of Chongqing Medical University (CN)
- National Center for Spinal Disorders (HU)
- Shanghai First People's Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Huashan Hospital (CN)
- Zhejiang University (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-26
- DOI
- https://doi.org/10.1038/s41467-026-76032-2
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- Fudan University
- Science and Technology Commission of Shanghai Municipality
- National Key Research and Development Program of China
- Natural Science Foundation of Zhejiang Province