Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent antitumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.
Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B. Heimberger, Peiwen Chen
Title and authors | Publication | Year |
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The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies
Vijayanathan Y, Ho IA |
International Journal of Molecular Sciences | 2025 |
Microenvironmental Drivers of Glioma Progression
Jang HJ, Park JW |
International Journal of Molecular Sciences | 2025 |
Epigenetic reprogramming and antitumor immune responses in gliomas: a systematic review.
Riyas Mohamed FR, Yaqinuddin A |
Medical oncology (Northwood, London, England) | 2025 |