Abstract Glioblastoma (GBM) tumors remain a lethal brain malignancy largely due to their ability to resist chemotherapy and reprogram immune cells to suppress anti-tumor responses. However, the origin and regulation of these immune cells, particularly the macrophages infiltrating lateral ventricle contacting tumors, remain unclear. Using ex vivo mechanistic assays with primary GBM tumor conditioned media (N=10) and primary human peripheral blood monocytes, we show that blood-derived monocytes can be instructed by GBM-derived factors to adopt an immunosuppressive macrophage phenotype. We identify IL-8 as a key cytokine driving the formation of CD32+ CD163+ CD206+ suppressor macrophages. Antibody-mediated blockade of soluble IL-8 in GBM tumor conditioned media leads to significantly decreased expression of this immunosuppressive phenotype, highlighting IL-8 as a crucial regulator of macrophage identity in aggressive GBM. Functionally, GBM-polarized macrophages suppress T cell proliferation, whereas macrophages polarized in the presence of IL-8 blockade show a reduced ability to suppress T cell responses. IHC analysis of 70 human GBM cases validate the expression of IL-8, and its receptors, CXCR1/CXCR2, across tumors in vivo, and reveals that IL-8 expression is enriched in more aggressive tumors that contact the lateral ventricle stem cell niche. Together, these findings suggest a new role for IL-8 as a modulator of macrophage identity and function, and a model in which blood-derived macrophages help maintain a suppressive microenvironment in aggressive GBM via IL-8 dependent macrophage polarization. This highlights IL-8 as a key therapeutic target to disrupt macrophage mediated induced immune suppression, which could potentially improve responses to immunotherapy in GBM patients. Citation Format: Stephanie Medina, Madeline J. Grider-Hayes, Asa Brockman, Rebecca A. Ihrie, Jonathan M. Irish. A new role for IL-8 as a driver of blood-derived macrophage reprogramming and immune suppression in human glioblastoma tumors abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr A001.
Medina et al. (2026) studied this question.