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Another study from researchers at Northwestern has also identified a mechanism by which glioblastoma suppresses the immune system. They found that tumor cells express a protein called podoplanin (PDPN), which binds to the receptor CLEC5A on tumor-associated macrophages in hypoxic, necrotic regions of the tumor. This interaction activates the Syk-JAK-STAT3 signaling pathway, driving macrophages into an immunosuppressive state that helps the tumor evade immune attack and is associated with worse patient outcomes. In mouse models, blocking CLEC5A or inhibiting Syk signaling reduced immune suppression, slowed tumor growth, and extended survival.
Importantly, some Syk inhibitors are already FDA-approved for other diseases, raising the possibility of faster clinical translation. The authors also suggest that reversing this macrophage-driven immunosuppression may not be sufficient on its own, and that future strategies may need to combine this approach with therapies that enhance cytotoxic T-cell activity, such as checkpoint inhibitors, in order to improve immune recognition and tumor targeting in GBM.