Glioblastoma stem cell–immune microenvironment crosstalk: molecular mechanisms and therapeutic opportunities

Abstract

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant primary brain malignancies, with limited improvement in long-term survival despite advances in multimodal therapy. Glioblastoma stem cells (GSCs) are central to tumour initiation, recurrence and therapeutic resistance, but their malignant properties are not determined by intrinsic programmes alone. Increasing evidence indicates that reciprocal interactions between GSCs and the tumour immune microenvironment (TIME) establish a dynamic ecosystem that promotes stemness, immune escape and treatment resistance. In this review, we summarise the molecular and cellular mechanisms underlying GSC – TIME crosstalk, with emphasis on tumour-associated macrophages, myeloid-derived suppressor cells, T cells, regulatory T cells, natural killer cells, B cells, plasma cells and neutrophils. We highlight major signalling and metabolic networks, including B2M/TGF-β1, IL8/CXCR2, IFI35/NF-κB, lactate/lactylation, IgG/FcγRIIA and m6A/LOXL2 signalling, as well as extracellular vesicle-mediated communication. We further discuss how these interactions sustain GSC stemness, facilitate metabolic adaptation, promote immune escape and contribute to resistance to radiotherapy, temozolomide and targeted therapies. Emerging therapeutic approaches—including tumour-associated macrophage/myeloid-derived suppressor cell (TAM/MDSC) reprogramming, metabolic and epigenetic intervention, immune checkpoint blockade, bispecific antibodies, chimeric antigen receptor T/natural killer (CAR-T/NK) cell therapy and extracellular vesicle-based delivery—are also evaluated. Finally, we discuss the importance of spatial heterogeneity, blood-brain barrier limitations and rational combination strategies. Understanding GSC-TIME crosstalk may provide a framework for developing more effective and biologically informed precision therapies for GBM.