Targeting glioma-associated microglia and macrophages: a new frontier in glioblastoma immunotherapy

Glioblastoma (GBM), the most aggressive and lethal subtype of glioma, remains therapeutically intractable despite advances in surgical and chemo-radiotherapy interventions. The highly immunosuppressive tumor microenvironment (TME) contributes significantly to treatment resistance and tumor recurrence. Among the predominant immune constituents, glioma-associated microglia and macrophages (GAMs) constitute a major cellular compartment, exerting profound influence on tumor progression, immune evasion, angiogenesis, and therapeutic response. These myeloid populations, derived from both yolk sac-origin microglia and bone marrow-derived macrophages, exhibit remarkable functional plasticity and are actively recruited, polarized, and reprogrammed by tumor-intrinsic and environmental cues. Recent studies have elucidated a range of molecular pathways, including chemokine signaling, metabolic reprogramming, and epigenetic modulation, that govern GAM behavior and sustain their tumor-supportive phenotype. Therapeutic strategies targeting GAM recruitment, depletion, or functional re-education toward an anti-tumor state are emerging as promising adjuncts to conventional and immune-based therapies. This review comprehensively explores the ontogeny, regulatory networks, and pathological roles of GAMs in GBM, with particular emphasis on novel immunotherapeutic approaches, including CSF-1R blockade, nanoparticle-mediated reprogramming, and oncolytic virotherapy. A deeper understanding of GAM-TME interactions will be critical to overcoming immunotherapy resistance and advancing precision immunomodulation in GBM.