Molecular heterogeneity of Glioblastoma-associated microglia and macrophages and myeloid-derived suppressor cells: Insights from single-cell omics and therapeutic implications

Glioblastoma (GBM) is characterized by a highly immunosuppressive microenvironment that is enriched with myeloid cell populations. Historically, these myeloid cells, particularly GBM-associated microglia/macrophages (GAMs) and myeloid-derived suppressor cells (MDSCs), were considered as pro-tumorigenic due to limitations in genomic technologies. However, advances in single-cell and spatial omics have revolutionized our understanding of the GBM immune landscape, uncovering extensive heterogeneity within the myeloid compartment. Studies utilizing murine models and patient-derived samples have demonstrated that GAMs and MDSCs exist along a spectrum of activation states, with both tumor-promoting and tumor-suppressive roles. These findings challenge the conventional view of myeloid cells in GBM and highlight their dynamic and context-dependent functions. This review summarizes key findings from single-cell and spatial-omics studies utilizing human GBM patient samples and highlighting the discovery of novel myeloid cell subsets, immunomodulatory programs, and tumor-niche specific myeloid subpopulations that have reshaped our understanding of the GBM immune landscape. We discuss how specific subpopulations interact with other cellular components of the tumor microenvironment to support tumor invasion, drive immunosuppression, and contribute to therapeutic resistance. Finally, we discuss therapeutic strategies informed by these insights, including subset-directed myeloid reprogramming, stimulating innate immune signaling and phagocytosis, and rational combinations of myeloid-targeted agents with chimeric antigen receptor (CAR) T-cell and other immune therapies to improve clinical outcomes in GBM.