Glioblastoma as a Neuro-Immune Network Disorder: Rethinking the Tumor Microenvironment, Neural Circuit Integration, and Therapeutic Resistance

Abstract

Glioblastoma, IDH-wildtype, CNS WHO grade 4, is a highly aggressive primary tumor of the central nervous system characterized by infiltrative growth, marked antigenic heterogeneity, and resistance to treatment. Despite advances in immunotherapy, clinical responses of glioblastoma remain transient and non-durable. Emerging evidence suggests that glioblastomas and related high-grade gliomas reside within a highly regulated neuro-immunologic tumor microenvironment (TME), which may contribute to these limitations. Within this microenvironment, structural, biochemical, and cellular remodeling reduce the efficacy of current immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitors, by impairing lymphocytic infiltration across the blood-brain barrier (BBB) and promoting T-cell exhaustion. The refractory nature of these tumors is further influenced by the neural circuitry that surrounds the TME. Through signaling molecules, such as glutamate and neuroligin-3 (NLGN3), neuronal activity can predispose the TME to an immunosuppressive baseline while simultaneously advancing tumor cell proliferation. These upstream signaling pathways and regionally heterogeneous neural interactions may contribute to diverse immune phenotypes and behaviors that ultimately influence clinical outcomes. These findings support a shift from a tumor-centered view to a neuro-immunological network model. Future therapeutic strategies will likely require a multidisciplinary approach that integrates neural signaling pathways, immune system modulation, and spatially defined landscapes, thereby reframing glioblastoma and related high-grade gliomas as a systems-level disorder rather than an isolated malignancy.