Abstract
Glioblastoma (GBM) possesses a profoundly immunosuppressive tumor microenvironment (TME) dominated by innate immune mechanisms. Tumor-associated macrophages (TAMs), microglia, and myeloid-derived suppressor cells (MDSCs) constitute the major immunosuppressive axis, promoting tumor progression through cytokine secretion (IL-10, TGF-β), metabolic reprogramming, and inhibition of cytotoxic immunity. These innate immune cells not only facilitate immune evasion but also impair adaptive T-cell responses, limiting the efficacy of current immunotherapies. Emerging evidence highlights the therapeutic potential of targeting innate immunity via TAM repolarization, MDSC depletion, and NK cell activation to reshape the immunosuppressive TME. This review summarizes the pivotal role of innate immunity in GBM pathogenesis and explores novel combinatorial strategies that integrate innate immune modulation with checkpoint blockade, oncolytic virotherapy, and metabolic interventions to overcome therapeutic resistance in this lethal malignancy.