Modeling gliomas with organoids: reconstructing the human neural microenvironment for translational neuro-oncology

Gliomas represent some of the most lethal and biologically complex tumors of the central nervous system, with poor outcomes across both adult and pediatric populations. Beyond tumor-intrinsic genetic alterations, glioma progression is increasingly recognized to be driven by dynamic interactions with the neural microenvironment, particularly through direct tumor-neuron communication. Studies of adult and pediatric gliomas, including glioblastoma (GBM) and diffuse midline glioma (DMG), using single-cell profiling and multi-omics technologies have revealed extensive tumor intrinsic and extrinsic heterogeneity, with phenotypically and genetically plastic tumor cells actively engaged with neurons, glia, vasculature, and immune compartments that collectively reshape the neural microenvironment to promote tumor growth, invasion, and therapy resistance. Conventional two-dimensional in vitro culture systems and in vivo animal models incompletely recapitulate these interactions, limiting mechanistic insights and constraining clinical translation to human patients. Recent advances in organoid technologies have addressed this gap, enabling the development of three-dimensional human-specific models of glioma-microenvironment interactions. Platforms such as iPSC-derived cerebral organoids, regionally patterned neural organoids, patient-derived glioma organoids and tumor-organoid co-culture systems capture essential features of these human diseases. These systems recapitulate tumor-neuron synaptic integration, diffuse invasion programs, activity-dependent tumor growth, hypoxia-structured niches, vascular interactions, and patient-specific therapeutic responses. In this review, we synthesize recent advances and biological insights gleaned across glioma organoid model systems and evaluate their strengths and limitations, including neurovascular and multi-lineage systems. We further highlight emerging innovations that enhance the physiological fidelity, reproducibility, and scalability of these models. Collectively, these platforms establish tumor microenvironment interactions as a central organizing principle of glioma biology and provide a strong foundation for mechanistic discovery, therapeutic development, and personalized neuro-oncology.