Targeting the Tumor Immune Ecosystem in Glioblastoma: Challenges and Innovations in Immunotherapy

ABSTRACT

Glioblastoma (GBM) is the most aggressive primary brain tumor, marked by poor prognosis and resistance to conventional therapies. A critical barrier to effective treatment lies in its highly immunosuppressive and heterogeneous tumor microenvironment (TME), which orchestrates immune evasion and therapeutic failure. Tumor‐associated macrophages (TAMs), particularly those with an M2‐like phenotype, sustain GBM proliferation, angiogenesis, and stem‐like cell maintenance. Dysfunctional T lymphocytes—especially the accumulation of regulatory T cells—further attenuate anti‐tumor immunity. Natural killer (NK) cells, dendritic cells, neutrophils, and myeloid‐derived suppressor cells (MDSCs) also contribute to immune suppression through distinct yet interconnected mechanisms. Despite the success of immunotherapies in other malignancies, immune checkpoint inhibitors, CAR‐T cells, and tumor vaccines have yielded limited efficacy in GBM, hindered by low neoantigen burden, antigenic heterogeneity, and poor immune infiltration. Overcoming these challenges requires a systems‐level understanding of the immunoregulatory circuits within the GBM TME and the development of combination immunotherapies guided by predictive biomarkers. This review systematically delineates the roles of immune components in GBM immunopathology and outlines the emerging therapeutic strategies.