Tumor-associated macrophages in glioblastoma: implications for immunotherapy

Abstract

Glioblastoma, IDH-wildtype, CNS WHO grade 4 (GBM) is the most aggressive primary malignant brain tumor in adults, with a median overall survival of approximately 15 months despite maximal surgical resection, radiotherapy, and chemotherapy with temozolomide. This therapeutic resistance is increasingly attributed to the immunosuppressive tumor microenvironment (TME), within which tumor-associated macrophages (TAMs) represent the most abundant infiltrating immune cell population. GBM-resident TAMs originate from two distinct lineages: embryonic brain-resident microglia and bone marrow-derived monocytes. They exhibit substantial phenotypic and functional heterogeneity beyond the classical inflammatory versus immunosuppressive dichotomy. Recent advances in single-cell RNA sequencing and spatial transcriptomics have identified multiple TAM states with distinct functional and spatial features, including GPNMB+ and VSIG4+ marker-defined subsets as well as a mesenchymal transcriptional program predominantly associated with monocyte-derived macrophages, each preferentially enriched in distinct spatial niches with substantial overlap and plasticity, and driving context-dependent immunosuppression through distinct metabolic and signaling pathways. Mechanistically, TAMs promote GBM progression via metabolic reprogramming, cytokine-mediated functional adaptation, and direct suppression of adaptive immunity. TAMs are also directly implicated in resistance to temozolomide and immunotherapies, including immune checkpoint inhibitors and chimeric antigen receptor T cell (CAR-T) therapy. This review comprehensively summarizes recent mechanistic insights and translational advances in TAM-targeted strategies, including TAM depletion via CSF1R inhibition, functional reprogramming toward inflammatory phenotypes, metabolic intervention, and nanoparticle-mediated precision drug delivery capable of penetrating the blood-brain barrier. Unlike earlier reviews that focused solely on TAM biology, this study explicitly connects the spatial distribution and functional heterogeneity of TAM subpopulations to therapeutic vulnerability, providing a practical framework for designing biomarker-driven, patient-specific combination immunotherapy trials.