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

Jiabo Li,¹ Xuya Wang,² Luqing Tong,³ Bo Feng,¹ Ling-kai Shih,¹ Steven M. Markwell,¹ Hannah Nuszen,¹ Tomasz Gruchala,¹ Nicholas G. Lam,¹ Petros Basakis,¹ Erika Ruiz-Yamamoto,¹ Deyu Fang,⁴ Roger Stupp,⁵ Xuejun Yang,² and Daniel J. Brat¹

Published June 2, 2026 - More info

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.

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