Metabolic cross-talk between glioblastoma and glioblastoma-associated microglia/macrophages: From basic insights to therapeutic strategies

Glioblastoma (GBM), a highly malignant “cold” tumor of the central nervous system, is characterized by its ability to remodel the GBM immune microenvironment (GME), leading to significant resistance to immunotherapy. GBM-associated microglia/macrophages (GAMs) are essential components of the GME. Targeting GAMs has emerged as a promising strategy against GBM. However, their highly immunosuppressive nature contributes to GBM progression and drug resistance, significantly impeding anti-GBM immunotherapy. Accumulating evidence suggests that metabolic reprogramming accompanies GBM progression and GAM polarization, which are in turn driven by specific metabolic abnormalities and altered cellular signaling pathways. Importantly, metabolic crosstalk between GBM and GAMs further promotes tumor progression. Clarifying and disrupting this metabolic crosstalk is expected to enhance the antitumor phenotype of GAMs and inhibit GBM malignant progression. This review explores metabolism-based interregulation between GBM and GAMs and summarizes recent therapeutic strategies targeting this crosstalk, offering new insights into GBM immunotherapy.