Organoids to Model Tumor Microenvironment in Progression of Pathogenesis and Treatment Resistance in Glioblastoma Multiforme

Glioblastoma multiforme (GBM) remains the most aggressive and therapeutically intractable primary brain tumor, with many patients experiencing rapid relapse despite maximal surgical resection followed by standard chemoradiation. This persistent failure reflects the convergence of profound tumor-intrinsic genetic heterogeneity and a highly dynamic, spatially structured, and immunosuppressive tumor microenvironment (TME). Together, these forces create strong selective pressures that fuel tumor evolution, intratumoral diversity, phenotype plasticity, diffuse invasion, and robust resistance to therapy. The TME of GBM is orchestrated through a complex interplay between diverse cellular constituents, including tumor-associated macrophages, reactive astrocytes, endothelial cells, pericytes, and GBM stem cells, and non-cellular components such as extracellular matrix remodeling, hypoxia, metabolic and nutrient gradients, and spatially patterned cytokine and chemokine signaling networks. Additionally, heterogeneity in blood–brain barrier (BBB) and blood–tumor barrier (BTB) complicates drug delivery and immune surveillance, reinforcing therapeutic resistance and regional tumor adaptation. Conventional two-dimensional cell cultures and animal models fail to sufficiently capture these multiscale, patient-specific interactions, limiting their translational predictive power. In this narrative review, we synthesize recent advances in GBM organoid technologies as physiologically relevant, three-dimensional platforms that more faithfully recapitulate TME for driving tumor evolution and treatment resistance. We compare complementary organoid strategies, including patient-derived GBM organoids that preserve native cytoarchitecture, cerebral organoid co-culture systems that reconstruct tumor–brain interactions, and advanced platforms incorporating immune and vascular features such as air–liquid interface cultures, microglia-enriched systems, and BBB/BTB-integrated models. Finally, we highlight emerging innovations such as spatial transcriptomics, organoid-on-a-chip systems, live imaging coupled with lineage tracing, genome engineering, and artificial intelligence integration that collectively position GBM organoids at the forefront of precision neuro-oncology, reproducing TME, enabling dynamic mapping of tumor evolution, and accelerating patient-specific therapeutic discovery.