Credit: Association of Basic Medical Sciences of FBIH

Glioblastoma (GBM) is the most aggressive and lethal form of brain cancer, with a median survival of only 15 months despite intensive treatment. Current therapies—including surgery, radiation, and chemotherapy—offer limited long-term benefit, and immune-based treatments have so far shown minimal success. The complexity of the tumor's microenvironment and its ability to suppress immune responses contribute to the poor prognosis.

In a new study published in Biomolecules and Biomedicine, researchers have identified two genes—CD44 and TNFSF14—as key contributors to GBM's ability to evade immune detection.

The findings offer new insight into the tumor's immunosuppressive landscape and suggest potential targets for more effective, personalized treatments.

Mapping GBM's immune suppression pathways

Using a network-based analysis of PD-L1—a protein known for dampening immune activity in tumors—the research team explored gene interactions in GBM tissue. CD44 and TNFSF14 were consistently overexpressed in GBM compared to lower-grade gliomas and healthy brain tissue. Both genes also showed strong associations with poor patient survival.

These results were supported by experimental validation using human tumor samples. CD44 and TNFSF14 distinguished GBM from normal brain tissue with high accuracy, suggesting potential as diagnostic biomarkers.

Subtype and immune associations

Further analysis revealed that these genes are especially elevated in the mesenchymal subtype of GBM, which is known for its aggressive growth and greater resistance to treatment. The researchers also found that CD44 and TNFSF14 expression correlated with increased levels of regulatory T cells and inactive natural killer (NK) cells—markers of a suppressed immune environment.

Notably, CD44 showed a moderate positive correlation with PD-L1 expression, further connecting it to known immune evasion pathways.

Toward new therapeutic strategies

The study highlights CD44 and TNFSF14 not only as biomarkers but also as possible therapeutic targets. CD44 is linked to tumor stem cells and invasion, while TNFSF14 may regulate immune cell infiltration and checkpoint activity. Together, these genes could help guide the development of immunotherapies better suited to GBM's unique biology.

While the findings are promising, the authors stress the need for further functional research, including gene knockout studies and immune co-culture models, to fully understand how these genes modulate immune responses in GBM.

This work provides a clearer picture of how GBM suppresses the immune system and adapts to therapy. By uncovering the role of CD44 and TNFSF14 in the tumor microenvironment, the study opens new directions for overcoming one of the biggest hurdles in brain cancer treatment.

More information: Alja Zottel et al, TNFSF14 and CD44 are overexpressed in glioblastoma and associated with immunosuppressive microenvironment, Biomolecules and Biomedicine (2025). DOI: 10.17305/bb.2025.11791