Immune niches in brain tumors: glial–immune cell interactions and spatial microdomains

Abstract

The immune microenvironment of brain tumors is characterized by remarkable diversity, where immune cells are not randomly distributed but are systematically organized into specific spatial microdomains. This spatial order is primarily orchestrated by glial cells, including astrocytes, microglia, and oligodendrocyte-lineage cells, which actively shape the local immune landscape by determining the position and activation states of infiltrating immune populations. To reflect the latest conceptual advances, this review first details the complex interaction networks through which glial cells directly modulate T-cell function and shape myeloid cell properties via cytokine signaling and metabolic regulation. We then examine how these active cellular communications synergize with the temporal process of tumor immunoediting and physical microenvironmental stressors (such as hypoxia) to drive the formation and physical anchoring of these immune niches. Consequently, these structurally established domains mature into functionally distinct, heavily immunosuppressive hubs that foster local T-cell exhaustion and coordinated immune escape. Because these niches are dynamically evolving ecosystems rather than static entities, they present profound architectural barriers, directly contributing to the heterogeneous and often limited responses to current immunotherapies. By integrating these spatial and temporal dynamics into a comprehensive conceptual framework, this review highlights the urgent clinical need to shift toward multidimensional, niche-disrupting therapeutic strategies, ultimately aiming to improve immunotherapy efficacy and clinical outcomes for patients with brain tumors.