Osteoclasts intercept meningeal lymphatic paths for dural metastasis

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. Osteoclast-derived angiopoietin-2 in the dura mater impairs lymphatic vessel function and weakens anti-tumour immunity against dural metastases, which offers new therapeutic approaches to restore meningeal lymphatic function through selective osteoclast targeting.