A deadly brain cancer that may not stay local
Glioblastoma, the most aggressive form of brain cancer, is revealing a new and troubling dimension: it appears to interact with the body’s immune system in ways that go beyond the brain itself. In a study published in Nature Neuroscience, scientists from the Montefiore Einstein Comprehensive Cancer Center (MECCC) and the Albert Einstein College of Medicine report that glioblastoma not only invades brain tissue but also erodes the skull bone, alters the skull’s marrow, and disrupts immune processes. The researchers also found that drugs designed to curb skull-bone loss unexpectedly made the cancer more aggressive in their mouse models, underscoring the complexity of glioblastoma’s relationship with the body’s defenses.
“Our work shows that this notoriously hard-to-treat brain cancer interacts with the immune system in a way that may help explain why therapies targeting glioblastoma as a strictly local disease have often failed,” said Jinan Behnan, Ph.D., the corresponding author and an assistant professor at Einstein and MECCC. “This discovery could point toward new strategies that address the tumor as a systemic condition, not just a brain lesion.”
A matter of marrow
Like many bones, the skull houses marrow where immune and blood cells form. Behnan’s team was spurred by recent findings that the skull and brain share ultra-thin channels that permit molecules and cells to travel between the skull marrow and the brain. In mouse models of two glioblastoma types, the tumors caused erosion of skull bones, especially along sutures where skull segments fuse. The pattern of erosion was distinctive to malignant intracranial tumors and did not mimic what is seen after strokes or other brain injuries. In human patients, CT scans showed skull thinning in the same regions identified in mice, suggesting a parallel process in people with glioblastoma.
The immune tilt in skull marrow
Using single-cell RNA sequencing, the researchers observed a dramatic reshaping of the skull marrow’s immune landscape. The skull marrow in the presence of glioblastoma produced far more pro-inflammatory myeloid cells, nearly doubling neutrophils, while several antibody-forming B cell types and other B cells were markedly reduced. The team proposes that the skull-to-brain channels allow a flood of inflammatory cells from the skull marrow into the tumor, making glioblastoma more aggressive and harder to treat.
“The skull-to-brain channels enable a influx of inflammatory cells from the skull marrow into the tumor,” noted E. Richard Stanley, Ph.D., a co-author and professor at Einstein. “This shift toward inflammation appears to fuel tumor progression and may help explain why current therapies targeting glioblastoma locally have limited success.”
The authors emphasize that restoring a balanced immune environment in the skull marrow could be a key therapeutic direction. Potential strategies include reducing the production of pro-inflammatory neutrophils and monocytes while boosting the generation of T and B cells, thereby reestablishing the immune equilibrium that tumors often disrupt.
A systemic view and regional differences
The study also uncovered a striking systemic element: glioblastoma did not affect all marrow equally. While skull marrow showed gene activation that boosted inflammatory immune cells, the femur marrow responded differently, with cancer-associated gene changes tending to suppress the production of several immune cell types. This finding supports the idea that glioblastoma is not merely a local brain cancer but a systemic disease capable of reshaping immune environments across the body.
Implications for treatment and future directions
The findings carry important implications for future therapies. Treatments that aim to protect skull bone without considering their broader immune consequences may inadvertently worsen disease course. Instead, researchers are exploring approaches to rebalance skull marrow immune populations—reducing inflammatory neutrophils and monocytes while preserving or enhancing T and B cell production. Such strategies could complement existing surgery, chemotherapy, and radiation, potentially improving outcomes for patients diagnosed with glioblastoma each year—roughly 15,000 in the United States—with current median survival around 15 months.
Looking ahead
While the work is preclinical, it opens a new avenue for understanding how glioblastoma interacts with the body’s immune architecture. By viewing glioblastoma as a systemic disease with skull-brain marrow connectivity, scientists hope to design therapies that address both tumor biology and the body’s immune response—offering a path toward more effective and durable treatments.
