The Peri-necrotic Niche of Glioblastoma Drives Tumor-associated Macrophage Polarization and Immunosuppression via Podoplanin-mediated CLEC5A Activation

Glioblastoma, IDH-wildtype (GBM, WHO grade 4) is the most common malignant glioma in adults and is characterized by a hypoxic and immunosuppressive tumor microenvironment (TME). Bone marrow-derived tumor-associated macrophages (TAMs) dominate the immune landscape in GBM and are recruited to the peri-necrotic niche following the onset of necrosis. CLEC5A has the strongest association with poor clinical outcome among immune-related genes in GBM, and is preferentially expressed in hypoxic, peri-necrotic TAMs. CLEC5A overexpression promotes TAM polarization toward an immunosuppressive phenotype, and secretion of immunoregulatory cytokines. Using an RCAS/tv-a GBM model with bone marrow transplantation from Clec5a -/- donor mice, we demonstrated that CLEC5A loss prolongs survival, delays tumor progression, and attenuates TME immunosuppression. Mechanistically, podoplanin (PDPN) expressed on glioma cells directly engages CLEC5A and triggers downstream Syk-JAK-STAT3 signaling in TAMs. Pharmacologic Syk inhibition suppresses glioma growth, diminishes TAM infiltration and polarization, reverses the immunosuppressive TME, and prolongs survival in vivo . Collectively, our findings indicate that the PDPN-CLEC5A-Syk-STAT3 axis orchestrates TAM polarization and TME immunosuppression in the peri-necrotic niche of GBM, highlighting CLEC5A/Syk as a promising therapeutic target for reversing the immunosuppressive TME and improving outcomes.