A new study has uncovered a key mechanism that helps one of the deadliest brain cancers evade the immune system, according to the study published in The Journal of Clinical Investigation.

Glioblastoma is the most common malignant brain tumor in adults and remains notoriously difficult to treat. Current therapies demonstrate limited success, and newer immunotherapies have largely failed to improve outcomes. Scientists say one major reason is the tumor’s ability to create an environment that suppresses the body’s immune response.

“Glioblastoma progresses very rapidly and is quickly fatal,” said the study’s senior author, Daniel Brat, MD, PhD, the chair and Magerstadt Professor of Pathology. “All attempts to direct therapy at specific mechanisms haven’t worked up to this point; even breakthroughs in immuno-oncology with checkpoint inhibitors haven’t worked for brain tumors.”

Unlike many cancers where immune cells infiltrate and attack tumors, glioblastoma largely evade those cells, Brat said. In particular, cytotoxic T-cells — the immune system’s primary cancer fighters — are scarce.

“They’re barely there,” Brat said. “They are a minuscule population within the tumor and are excluded. Until we find a way to increase their numbers and function, we’re going to have a challenging time improving outcomes.”

Instead, the tumor is dominated by tumor-associated macrophages (TAMs), a type of immune cell that can promote cancer growth rather than fighting it. These macrophages are especially concentrated in oxygen-deprived, necrotic regions of the tumor.

“It’s the onset of necrosis that turns these tumors into an immunosuppressive environment,” Brat said. “By most studies, this is the most macrophage-rich signature of all cancers. Unfortunately, those macrophages are not fighting the disease, they’re promoting it.”

In the study, Brat and his collaborators systematically searched for immune-related genes tied to poor outcomes in glioblastoma.

The team identified a receptor called CLEC5A as a central driver of this immunosuppressive environment, according to the findings. The protein was highly expressed in macrophages located in hypoxic, peri-necrotic regions of glioblastoma and was strongly associated with poor patient survival.

The investigators then demonstrated that CLEC5A actively programs macrophages into an immunosuppressive state, prompting them to release signals that dampen immune responses.

The team also uncovered how this process begins. Glioblastoma cells produce a protein called podoplanin (PDPN), which binds to CLEC5A on macrophages. This interaction activates a signaling cascade — known as the Syk-JAK-STAT3 pathway — that drives immune suppression.

“We identified PDPN as a ligand that activates CLEC5A and triggers downstream signaling,” said the study’s first author Jiabo Li, MD, PhD, research assistant professor of Pathology in the Division of Experimental Pathology. “This promotes macrophage polarization toward an immunosuppressive phenotype.”

To test whether blocking this pathway could improve outcomes, investigators used mouse models of glioblastoma. They found that removing CLEC5A or inhibiting the Syk signaling protein slowed tumor growth, reduced immune suppression and extended survival.

Some Syk inhibitors are already FDA-approved for other conditions, raising the possibility of faster clinical translation, Brat said.

While the results are promising, the study’s authors say targeting this pathway alone may not be enough. The next step is combining this approach with therapies that actively boost T-cell responses.

“We think we need to not only reverse immunosuppression, but also promote cytotoxic T-cells,” Brat said. “We plan to combine this strategy with checkpoint inhibitors in the future.”

The team also hopes to confirm that reinvigorated T-cells can specifically recognize and attack tumor cells, an essential step toward designing effective immunotherapies.

“Glioblastoma has been incredibly challenging to tackle,” said Brat, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “But understanding how these tumors create an immunosuppressive environment gives us a path forward.”

The study was supported by funding from the National Institutes of Health National Cancer Institute under awards R01CA214928, R01CA247905, R01CA295560 and P50CA221747 SPORE for Translational Approaches to Brain Cancer.