Translational Models for Glioblastoma: Revolutionizing Drug Development and Personalized Medicine through Clinical...

Glioblastoma (GBM) remains one of the most aggressive and treatment resistant brain tumors and continues to present major challenges for effective therapeutic development. The failure of numerous late-stage clinical trials highlights the limited predictive value of conventional preclinical models. Although established cell lines, two-dimensional cultures, and animal models have been extensively employed, existing platforms fail to adequately recapitulate the complex tumor microenvironment, blood brain barrier function, and interpatient heterogeneity that drive therapeutic resistance in GBM. To address this translational limitation, advanced experimental systems have been developed to more accurately reproduce key features of the human GBM microenvironment through the integration of microengineering approaches, biomaterials, and patient derived cells. This review focuses on recent advances in microfluidic GBM chip models and three-dimensional bioprinted GBM platforms, while also summarizing a broad range of in vitro and in vivo model systems extending from conventional 2D cultures and organoids to animal-based platforms. Microfluidic and 3D bioprinting technologies enable controlled reconstruction of critical biophysical and biochemical features of the GBM microenvironment. These systems allow regulation of oxygen availability, drug exposure, and cellular interactions within engineered tumor constructs. As a result, patient specific GBM models with heterogeneous architectures can be generated with improved biological relevance and closer resemblance to in vivo tumor behavior. In parallel, in vivo systems remain indispensable for capturing systemic pharmacokinetics, host immune responses, and organ level toxicity. Among these, mouse models encompassing syngeneic, xenograft, and genetically engineered mouse models (GEMMs) continue to serve as the foundation of preclinical GBM research, while larger animal models have been explored to better approximate the physiological and immunological features of human disease. Overall, this review discusses recent advances in GBM model development across microengineered in vitro platforms and in vivo animal systems and examines their potential to enhance translational accuracy, accelerate drug discovery, and support personalized therapeutic strategies. By emphasizing the technological scope and clinical relevance of these platforms, this work aims to provide practical guidance for the rational selection and integration of GBM model systems in the discovery and optimization of next generation therapeutics.