Osteoclasts intercept meningeal lymphatic paths for dural metastasis

  • Nature. 2026 Oct;658(8137):1025-1035. doi: 10.1038/s41586-026-11082-6.
Rui Zeng  #  1  2 ,  Jiaxu Zhao  #  3 ,  Haibao Peng  #  1  2 ,  Jiadong Ma  1  2 ,  Shuyi Hua  2 ,  Youming Zeng  1  2 ,  Xiaohui Li  1  2 ,  Yang Huang  1  2 ,  Cheng Li  1  2 ,  Jiahui Yang  1  2 ,  Hongru Chen  2 ,  Xue Feng  4 ,  Qiangqiang Zhang  5 ,  Liang Chen  6  7  8 ,  Yudan Chi  9  10
Affiliations
  • 1. Department of Neurosurgery of Huashan Hospital, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Fudan University, Shanghai, China.
  • 2. Department of Radiology, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Geriatrics and Gerontology, Fudan SANS Neuroscience Center, Fudan University, Shanghai, China.
  • 3. School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China. [email protected].
  • 4. Laboratory Animal Center, Fudan University, Shanghai, China.
  • 5. Department of Biotechnology and Biomedicine, Advanced Model Animal Research Center, Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, China.
  • 6. Department of Neurosurgery of Huashan Hospital, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Fudan University, Shanghai, China. [email protected].
  • 7. Tianqiao and Chrissy Chen Institute Clinical Translational Research Center, Shanghai, China. [email protected].
  • 8. Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China. [email protected].
  • 9. Department of Neurosurgery of Huashan Hospital, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Fudan University, Shanghai, China. [email protected].
  • 10. Department of Radiology, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Geriatrics and Gerontology, Fudan SANS Neuroscience Center, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42816624 DOI: 10.1038/s41586-026-11082-6
Abstract

Dural metastasis (DM)-a devastating complication of advanced malignancies such as breast and lung cancers-is defined by tumour cell infiltration into the dura mater and presents unique clinical challenges distinct from brain metastasis1,2. Our study unveils a, to our knowledge, previously unrecognized role of meningeal lymphatic dysfunction in DM pathophysiology, providing a new conceptual framework for this unique form of metastatic disease. Distinctive cranial erosion patterns, identified through clinical imaging, set DM apart from other metastases. Using a new mouse DM model, we discovered significant impairments in meningeal lymphatic drainage associated with tumour progression. Through single-cell RNA Sequencing analysis, we characterized the tumour micro-environmental landscape of DM, highlighting the predominant immunosuppressive tactics driven by cancer-related osteoclasts (OCs). Notably, large OCs localize specifically at the skull-tumour interface, whereas smaller OCs permeate intratumoral regions. We found that these OCs disrupted lymphatic paths significantly, and targeting them therapeutically led to restoration of meningeal lymphatic structure and function in DM, thereby augmenting anti-tumour immune responses. Mechanistically, we demonstrated that OC-derived angiopoietin-2 contributes to the dysregulation of meningeal lymphatic drainage in the DM model. Our findings suggest a new therapeutic approach to restore meningeal lymphatic function through selective OC targeting, offering promising avenues for enhancing anti-tumour immunity and improving clinical outcomes in patients with DM.

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