Glioma microenvironment: Cellular crosstalk, immunosuppression, and novel therapeutic perspectives

Glioma, the most aggressive primary brain malignancy, arises from glial cells within the central nervous system. Despite aggressive treatment, the prognosis remains poor, with all patients expected to experience recurrence. An important component of glioma growth is the interaction with the other cells in the brain environs. This complex ecosystem, termed the tumor microenvironment (TME), includes recruited immune cells and the resident cells in the central nervous system. Glioma cells recruit myeloid cells and reprogram their phenotype to fuel tumor growth. Tumor cells and reprogrammed myeloid cells further suppress adaptive immune responses. Additionally, glioma co-opts normal brain cells-including endothelial cells, neurons, and astrocytes-to create a microenvironment favoring tumor progression. Following this phenotypic shift, normal cells synergize with tumor cells to drive proliferation, invasion, immunosuppression, and angiogenesis. This review integrates recent advances in understanding the multidimensional interactions within the glioma TME, including insights gained from single-cell and spatial transcriptomics approaches that reveal its heterogeneous architecture and functional niches. By elucidating the underlying cellular and molecular mechanisms, we highlight how targeting the TME offers potential therapeutic opportunities to overcome treatment resistance and improve patient outcomes.