Montefiore Einstein investigators have led a multi-institutional study revealing that glioblastoma extends beyond the brain to actively erode the skull and fundamentally alter the immune environment of skull bone marrow, uncovering a previously unrecognized systemic dimension of the disease. Published in Nature Neuroscience in October 2025, the study demonstrates that glioblastoma induces widespread disruption of the calvarial bone (the skull) and alters immune cell activity within skull marrow. These changes were observed not only in animal models but also confirmed in patients with glioblastoma, where imaging revealed an average 20% reduction in skull thickness, independent of tumor size, tumor location, age or gender.

Glioblastoma multiforme is the most common primary brain tumor in adults and the most aggressive malignant primary tumor of the central nervous system. Despite advances in treatment, it remains incurable, with a median survival of approximately 15 months. Although glioblastoma has been described as a systemic disease that affects immune organs, the nature and extent to which it alters the skull marrow homeostatic environment and impacts its immune niche have not been well studied.

Using high-resolution micro-computed tomography (micro-CT) imaging, single-cell ribonucleic acid (RNA) sequencing and deep molecular profiling of immune cells in murine models, the investigators found that glioblastoma activates bone disruption and osteoclasts, bone-resorbing cells, in several anatomical regions of the calvarium that delineate osteogenic edges adjacent to the skull sutures, resulting in reduced bone density and thickness. Glioblastoma was also shown to induce specific bone morphometry changes in the calvarium and to increase the number and diameter of skull channels.

At the same time, glioblastoma was shown to alter the immune landscape of skull marrow and long-bone marrow, inducing differential changes across lymphoid and myeloid lineages, including expansion of neutrophils and deterioration of various B-cell subsets. The visualized ossified skull channels revealed an increase in both number and diameter, suggesting that they may play a role in immune cell trafficking to brain tumors and that glioblastoma can remotely influence immune behavior at anatomical sites far from the primary lesion.

Importantly, preclinical data from the study demonstrated that in vivo pharmacologic inhibition of bone resorption, using certain U.S. Food and Drug Administration (FDA)-approved drugs for osteoporosis including the osteoclast inhibitors zoledronic acid and anti-receptor activator of nuclear factor kappa beta ligand (RANKL) antibody, reduced skull bone abnormalities but promoted tumor progression in mesenchymal subtype tumors. When combined with an immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1), osteoclast inhibition eliminated the survival benefit observed with checkpoint blockade alone, reducing activated T-cell numbers and increasing inflammatory neutrophil numbers. These findings highlight the need to consider skull bone and marrow biology when evaluating therapeutic strategies, particularly in the context of immunotherapy.

“This study shows that glioblastoma affects much more than just the brain itself,” said Jinan Behnan, PhD, Assistant Professor of Neurological Surgery at Albert Einstein College of Medicine. “Together, these findings provide insight into how brain tumors impact skull bone and the immune environment.”

The study reflects Montefiore Einstein’s continued leadership in translating leading-edge discovery into insights that inform the future of neuro-oncology and immunotherapy. Montefiore Einstein is ranked in the top 1% of all hospitals in the nation for neurology and neurosurgery and cancer care according to U.S. News & World Report. The program is fully integrated with Montefiore Einstein Comprehensive Cancer Center, among the elite 1% of National Cancer Institute (NCI)-designated comprehensive cancer centers in the U.S.

References

Dubey A, Yamashita E, Stangeland B, et al. Brain tumors induce widespread disruption of calvarial bone and alteration of skull marrow immune landscape. Nature Neuroscience. 2025;28(11):2231–2246. doi:10.1038/s41593-025-02064-4.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12586139

Brzostowicki D. How glioblastoma “hijacks” the skull, and why treatments fail. Medscape Medical News. December 19, 2025.
https://www.medscape.com/viewarticle/how-glioblastoma-hijacks-skull-and-why-treatments-fail-2025a1000zsi

Rosen M. Brain cancer can dissolve parts of the skull. Science News. October 24, 2025.
https://www.sciencenews.org/article/brain-cancer-glioblastoma-erode-skull