Neuroimmune communication: from CNS-resident cell networks to the glioblastoma microenvironment

Abstract

Neurons, glial cells, and immune cells engage in extensive bidirectional communication within the central nervous system (CNS) through shared receptors, ligands, and secreted mediators. Glial cells — particularly astrocytes and microglia — serve not merely as structural support but as central immunomodulatory hubs that relay neural signals to immune effectors. In the context of CNS malignancies, glioblastoma (GBM) co-opts these neuroimmune networks to establish an immunosuppressive tumor microenvironment. This narrative review is organized around five interconnected axes. After summarizing the receptor and ligand repertoires of CNS-resident cell types, we examine (i) the neural inputs that reach glioblastoma and the reciprocal signals the tumor returns to the neural compartment; (ii) the remodeling of glial cells and glioma-associated macrophages/microglia; (iii) the innate and adaptive immune suppression that follows, including a “chemical–cellular” suppressive architecture; (iv) the blood–brain barrier and neurovascular interface that constrain immune access; and (v) the therapeutic opportunities arising from each of these layers.