Macrophage immunometabolism in glioblastoma: from microglial reprogramming to B cell dysfunction

Glioblastoma (GBM) is an aggressive primary brain tumor whose progression and resistance to therapy are driven not only by malignant cells but also by extensive metabolic and immunological remodeling of the tumor microenvironment (TME). Among the most abundant immune populations within the GBM TME are tumor-associated macrophages (TAMs), including resident microglia and infiltrating monocyte-derived macrophages. Under physiological conditions, microglia preserve central nervous system (CNS) homeostasis through immune surveillance, phagocytosis, synaptic remodeling, and metabolic regulation. However, exposure to tumor-derived signals, hypoxia, and nutrient deprivation reprograms these cells toward predominantly immunosuppressive phenotypes that promote tumor growth, angiogenesis, immune evasion, and therapeutic resistance. Emerging evidence demonstrates that TAMs engage in extensive bidirectional communication with B cells, further shaping the immunosuppressive landscape of GBM. Macrophages regulate B-cell activation, survival, differentiation, and antigen presentation through cytokines, chemokines, growth factors, and direct cell-cell interactions, while B cells influence macrophage polarization through antibody production and inflammatory signaling. Simultaneously, metabolic competition within the TME, characterized by glucose depletion, lactate accumulation, and hypoxia, impairs B-cell effector functions, diminishes antigen presentation and humoral immunity, and promotes the development of regulatory B cells (Bregs), thereby reinforcing immune suppression and facilitating tumor progression. This review summarizes the physiological functions of microglia, the metabolic and functional reprogramming of tumor-associated myeloid populations in GBM, and the emerging evidence surrounding TAM–B-cell interactions. By integrating findings from GBM with mechanistic insights from other tumor and disease contexts, we examine how metabolic constraints within the TME could potentially influence macrophage–B-cell crosstalk. We propose this relationship as a novel and testable framework for understanding immune regulation in GBM, while distinguishing established GBM-specific mechanisms from pathways supported primarily by evidence in other disease settings. Finally, we discuss how macrophage immunometabolism and its potential intersection with B-cell function may represent areas for future investigation and therapeutic exploration in GBM.