Glioblastoma Organoid Technology: Approach to Target the Complex Tumor Microenvironment with Promising Drug Responsiveness

Glioblastoma remains one of the most lethal brain tumors with limited therapeutic options and a dismal survival rate, largely due to its highly complex Tumor Microenvironment (TME) and frequent drug resistance. In response, three-dimensional (3D) organoid technology has emerged as a powerful tool for modeling glioblastoma, offering a physiologically relevant in vitro system that closely mimics the in vivo architecture, cellular heterogeneity, and drug response of human tumors. Unlike traditional 2D cultures or animal models, glioblastoma organoids enable highthroughput drug screening, personalized therapy testing, and early diagnostic research by preserving key features of the TME. However, despite their immense promise, current organoid models face substantial limitations, including the absence of immune components, functional vasculature, and region-specific neuronal subtypes, thereby restricting their full translational potential, especially for immunotherapy studies. Existing models, such as genetically engineered cerebral organoids (Neo- Cor) and glioblastoma spheroid co-cultures (GLICO), either fail to reflect patient heterogeneity or are constrained by time-intensive preparation. Additionally, patient-derived organoids may lose genetic fidelity over prolonged culture. The novelty of this work lies in its advocacy for engineered cell-based strategies and Adult Stem Cell (AdSC)-derived organoids to overcome these challenges. By enhancing the intrinsic properties of organoid cells and integrating endothelial and immune components, this approach offers a next-generation platform for more accurate modeling of glioblastoma, with greater relevance for drug responsiveness, chemosensitization studies, gene editing, and regenerative applications. This distinguishes the present work from previous studies by not only identifying the gaps in current organoid technologies but also proposing specific, actionable improvements that bring organoid culture closer to clinical translation in glioblastoma research.