Innate immune networks in glioblastoma: Cellular plasticity, immune crosstalk, and therapeutic implications

Glioblastoma (GB), defined here primarily as adult-type Isocitrate dehydrogenase-wildtype high-grade glioma, according to the 2021 World Health Organization classification, is an aggressive primary brain tumor characterized by local and systemic immunosuppression, therapeutic resistance, and poor clinical outcomes. Although considerable attention has focused on adaptive immune responses in GB, innate immune cells centrally regulate the tumor microenvironment. They may influence tumor progression, immune evasion, and treatment response. The strength of evidence varies substantially across innate immune populations, ranging from well-characterized myeloid compartments, such as tumor-associated macrophages, dendritic cells, myeloid-derived suppressor cells, and neutrophils, to less explored granulocytic and lymphoid subsets, including natural killer cells, innate lymphoid cells, eosinophils, mast cells, and basophils. In this review, we discuss the context-dependent roles of these cells in tumor surveillance and promotion, their interactions with GB stem-like cells, their contributions to immunosuppression and therapeutic resistance, and their potential relevance as prognostic biomarkers or therapeutic targets. By integrating clinical observations with experimental evidence, we highlight current strategies to reprogram innate immunity in GB and identify key limitations that must be addressed before innate immune-based approaches can be translated more effectively into clinical practice.