New Insights into Monocyte-Derived Macrophages in Glioblastoma.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by an immunosuppressive microenvironment that importantly contributes to treatment resistance. Monocyte-derived macrophages (MDMs), which comprise approximately 50% of the cellular population within the GBM microenvironment, represent a major subset of tumor-associated macrophages. These cells drive tumor progression by promoting angiogenesis, immune evasion, and the phenotypic transformation of tumor cells. MDM infiltration is mediated by specific signaling pathways and regulated by the disruption of the blood-brain barrier and tumor-associated hypoxia. Recent technological advances have uncovered substantial heterogeneity among macrophages, including hypoxia-induced, lipid-metabolizing, phagocytic, and interferon-activated subtypes. This functional diversity is shaped by tumor-specific genetic alterations and metabolic reprogramming. Therapeutic approaches focusing on MDMs include inhibiting their recruitment, enhancing phagocytic activity, employing genetically engineered macrophage, and modulating metabolic pathways. While preclinical studies suggest that these approaches may improve efficacy when combined with immune checkpoint inhibitors, the dynamic spatiotemporal heterogeneity and adaptability of macrophages within the tumor microenvironment remain substantial therapeutic challenges. Future development in combination therapies, integrating single-cell multi-omics, spatial metabolic profiling, and targeted interventions, will be critical to precisely modulate MDMs, overcome immune tolerance, and improve patient outcomes.