Glioblastoma (GBM) remains the most aggressive and lethal primary malignant tumor of the central nervous system (CNS) in adults. Patients with GBM show low sensitivity to immune checkpoint inhibitors (ICI) and tumor vaccines, which have achieved breakthroughs in other solid tumors, and related clinical trials have not yielded definitive survival benefits. Recent studies indicate that dural immune activity plays a crucial role in maintaining CNS homeostasis. Enhancing meningeal lymphatic vessel (MLV) drainage by overexpressing vascular endothelial growth factor-C (VEGF-C) has been shown to boost anti-GBM immunity and synergize with ICI therapy. However, the immunoregulatory function and mechanisms of the meningeal immune interface during GBM progression are not systematically understood, and therapeutic strategies targeting this site for CNS diseases remain underdeveloped.

On February 4, 2026, a research team led by Prof. Fan Bai (Biomedical Pioneering Innovation Center/ Peking-Tsinghua Center for Life Sciences / Peking University Beijing-Tianjin-Hebei Biomedical Pioneering Innovation Center) in collaboration with Prof. Nu Zhang's team (Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University) published a study titled "Meningeal blood vessel blockage enhances anti-glioblastoma immunity" in Cell. This study reveals for the first time that the dura, as a dynamic immune interface, can influence the progression of CNS tumors, expanding the current understanding of CNS tumor immunology. Based on this discovery, the research further proposes a novel strategy targeting the dura, opening a new avenue with translational potential for developing specific immunotherapies against CNS tumors.

1. Meningeal Blood Vessel Blockage (MBB) Fights GBM Progression via an Immune-Dependent Mechanism

The blood supply to the dura is independent of the brain parenchyma. The parenchyma is supplied by the internal carotid artery (ICA), while the dura is supplied by branches of the external carotid artery (ECA). Researchers established a mouse MBB model by performing bilateral ECA ligation. Evaluations using morphology, behavior, and high-throughput sequencing confirmed that MBB specifically modulates dural blood supply without significantly affecting parenchymal blood flow, brain function, or peripheral blood immune cell subsets.

Subsequently, using various MBB tumor-bearing mouse models—including intracranial orthotopic implantation models (GL261 and CT2A, with MBB performed either before or after tumor initiation), a spontaneous GBM mouse model, and a virally induced tumor model—the study demonstrated that MBB effectively inhibits tumor progression and significantly prolongs the survival of tumor-bearing mice. MBB treatment showed no benefit in immunodeficient mice, suggesting its anti-tumor function is mediated through an immune-dependent pathway (Figure 1).

Figure 1 MBB Significantly Prolongs the Survival of Tumor-Bearing Mice

To investigate the impact of MBB on the GBM tumor microenvironment (TME), researchers performed single-cell RNA sequencing (scRNA-seq) on tumors from MBB and sham-operated mice. The TME in MBB mice showed significantly enhanced T cell immune activation and inflammatory responses, characterized by increased CD8⁺ T cell infiltration, enhanced effector functions, cytotoxicity, and TCR signaling pathway activity. Additionally, myeloid cells exhibited a significantly elevated pro-inflammatory phenotype (Figure 2). These findings were further confirmed by flow cytometry and ex vivo co-culture functional assays.

Figure 2 MBB Significantly Improves the Tumor Microenvironment (TME) in Tumor-Bearing Mice

2. Dural Tissue-Resident Border-Associated Macrophages (rBAM) Exhibit Superior Antigen-Presenting Capacity under GBM Conditions

Comparing dural immune cell subsets between MBB and sham-operated tumor-bearing mice via scRNA-seq, border-associated macrophages (BAM) were identified as the most significantly altered population. Based on transcriptomic features, BAMs were classified into tissue-resident rBAMs (high expression of Lyve1, Folr2, Cd163) and circulation-derived cBAMs (high expression of Ccr2, Cd72, Acp5). These differences were further validated by immunofluorescence staining and in vivo tracing models (Figure 3).

Figure 3 Characterization of Border-Associated Macrophage (BAM) Subsets in the Dura

This study also generated the first single-cell atlas of the human dura in the context of GBM. Analysis revealed that GBM mediates extensive remodeling of the dural microenvironment (DME), manifesting as a global enhancement of inflammatory responses and adaptive immune responses, with observed activation of the TNF signaling pathway in various major immune cell types. Cross-species comparative analysis showed that the cellular markers and whole transcriptome profiles of the two BAM subsets are conserved between humans and mice. Using paired dura-tumor samples from GBM patients, researchers found a positive correlation between the proportion of dural rBAMs and the infiltration and effector function of CD8⁺ T cells within the tumor (Figure 4).

Figure 4 The Proportion of rBAM in the Dura Positively Correlates with Effector CD8+ T Cells in Tumors

Further ex vivo co-culture experiments revealed that under non-tumor conditions, rBAMs and cBAMs exhibited similar capabilities in antigen phagocytosis and T cell activation. However, under tumor conditions, these abilities of rBAMs were significantly enhanced, while cBAM performance showed no significant change. Subsequent cerebrospinal fluid (CSF) proteomic analysis indicated that the enhanced antigen-presenting capacity of dural rBAMs is mediated by immune complexes (ICs) abundantly present in the CSF under tumor conditions. These ICs bind to the neonatal Fc receptor (FcRn), which is highly expressed on rBAMs, thereby promoting their antigen-presenting function (Figure 5).

Figure 5 ICs-FcRn Mediates rBAM-Enhanced Tumor Immune Surveillance

3. MBB Promotes rBAM Expansion Post-Treatment, Enhancing T Cell Anti-Tumor Immunity via the Dura-CSF-TME Axis

Investigating changes in dural BAMs after MBB, researchers used whole-tissue immunofluorescence staining and flow cytometry to find that MBB treatment reduced the number of cBAMs while significantly increasing the number of rBAMs. Specific ablation of cBAMs in Ccr2-DTR-GFP mice via epidural diphtheria toxin (DT) injection confirmed that cBAM reduction triggers rBAM expansion. Further, they demonstrated that rBAM expansion is mediated by colony-stimulating factor 1 (CSF-1) secreted by dural fibroblasts. The reduction of cBAMs after MBB creates a CSF-1-enriched environment, driving rBAM proliferation. These results suggest a mutually regulatory mechanism between dural rBAMs and cBAMs maintaining homeostatic balance (Figure 6).

Figure 6 MBB Promotes rBAM Expansion by Regulating CSF-1 Availability

Using various in vivo models and multiphoton imaging, the study confirmed that dural rBAMs, as key antigen-presenting cells, capture tumor antigens from the CSF and present them to patrolling T cells, initiating a cascade of T cell activation and infiltration into the TME. MBB enhances the interaction along the dura-CSF-TME axis by modulating the quantity and function of rBAMs, thereby eliciting a stronger anti-tumor response.

4. MBB Synergizes with Immunotherapy to Enhance Anti-Tumor Immunity, and rBAM Abundance Predicts Clinical Prognosis

To evaluate the potential of combining MBB with existing therapies, researchers tested its synergistic effects in preclinical models. Given that the primary effect of MBB is the expansion of dural rBAMs, the study first explored the therapeutic effect of MBB combined with epidural administration of CSF-1. Results showed that the MBB+CSF-1 combination further inhibited tumor growth and significantly extended the overall survival of model mice. Flow cytometry analysis indicated that effector T cells in the TME exhibited a stronger effector phenotype after combination therapy.

Researchers further evaluated the effect of combining MBB with anti-PD-1 immune checkpoint inhibitors. Results showed that while MBB monotherapy could inhibit tumor volume and prolong survival, the combination of MBB and anti-PD-1 therapy further suppressed tumor growth and significantly improved survival benefits. Flow cytometry analysis of the TME revealed that effector T cells in the combination treatment group had the highest expression levels of cytotoxic factors (granzyme B, perforin) and cytokines (IFN-γ, TNF-α). These results collectively confirm the significant synergistic anti-tumor effects of MBB with either CSF-1 or anti-PD-1 therapy in GBM models.

To explore the clinical correlation between rBAM abundance and patient prognosis, researchers divided GBM patients into high-rBAM and low-rBAM groups based on the median rBAM proportion in a scRNA-seq cohort. Analysis found that patients with high rBAM levels (n=12) had significantly longer overall survival than those with low rBAM levels (n=11). The consistency between preclinical models and human patient data strongly supports the critical biological and clinical significance of dural rBAMs in GBM progression and highlights their important value as a therapeutic target for MBB and a potential prognostic biomarker (Figure 7).

Figure 7 MBB Combined with Immunotherapy Exhibits Significant Synergistic Effects

Summary

This study reveals for the first time that the dura, as a key dynamic immune interface in the CNS, can regulate the progression of CNS tumors through its immune activity. It expands the current understanding of CNS tumor immunology and proposes a novel surgical treatment strategy targeting the dura for GBM, providing a new avenue for immunotherapy of CNS tumors.

Prof. Fan Bai (BIOPIC, Peking University) and Prof. Nu Zhang (The First Affiliated Hospital of Sun Yat-sen University) are the co-corresponding authors. Prof. Xiuxing Wang (Nanjing Medical University) provided analytical samples and technical guidance for this study. Dr. Yixin Gao (The First Affiliated Hospital of Sun Yat-sen University), PhD candidate Yushan Peng (BIOPIC, Peking University), Dr. Jiying Cheng, and Dr. Xinyu Zhang (The First Affiliated Hospital of Sun Yat-sen University) are the co-first authors of the paper.

This project was funded by the National Natural Science Foundation of China (NSFC), Ministry of Science and Technology (MOST), Scientific Exploration Award.

Link: https://www.sciencedirect.com/science/article/abs/pii/S0092867425014941