Immune-angiogenic crosstalk in glioblastoma: Mechanisms and therapeutic opportunities.

Glioblastoma (GBM) remains the most aggressive and therapeutically challenging primary brain tumor and is characterized by strong heterogeneity, rapid progression, and poor clinical outcomes. Accumulating evidence indicates that the immune-angiogenic axis is a major contributor to GBM progression and therapeutic resistance, coordinating dynamic interactions among tumor cells, immune populations, and the vascular network within the tumor microenvironment (TME). Aberrant angiogenesis, driven primarily by vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and other proangiogenic mediators, promotes the formation of structurally abnormal and highly permeable blood vessels that worsen hypoxia, facilitate tumor invasion, impair immune cell trafficking, and limit clinical intervention. The GBM TME is characterized by profound immunosuppression, in which tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and dysfunctional lymphocytes promote immune evasion and tumor progression. Immune and angiogenic pathways are interconnected through reciprocal signaling networks that sustain vascular remodeling, reinforces immune evasion, and disease progression. This bidirectional crosstalk contributes to the limited efficacy of current therapies, including antiangiogenic agents and immune checkpoint inhibitors, by promoting adaptive resistance and tumor plasticity. Despite substantial advances in understanding the immune-angiogenic axis, important questions remain regarding the relative contributions of distinct cellular populations, the mechanisms underlying therapeutic resistance and the translation of emerging molecular insights into clinically effective therapies. This review critically synthesizes the established mechanisms of immune-vascular crosstalk while distinguishing emerging concepts supported primarily by preclinical evidence, including macrophage heterogeneity, spatial immune organization, and biomarker-guided therapeutic strategies. By integrating vascular biology, immune regulation, and therapeutic resistance into a unified conceptual framework, this review highlights the current knowledge, unresolved questions, and future opportunities for biomarker-guided combination therapies. Emerging technologies, including single-cell transcriptomics, spatial profiling, and artificial intelligence-assisted multiomics, are discussed as enabling platforms for patient stratification and precision therapeutic development rather than as therapeutic endpoints themselves.