Modeling glioblastoma niche-by-niche: recent advancements in bioengineering of organotypic models of glioblastoma for...

Glioblastoma (GBM) represents the most aggressive and recalcitrant primary malignancy of the central nervous system, characterized by profound intratumoral heterogeneity and a formidable capacity for adaptive therapeutic resistance. This phenotypic plasticity is orchestrated by the tumor microenvironment (TME), which functions as a dynamic clockwork mechanism wherein the hypoxic, perivascular, immune, and neural niches act as interconnected, functionally coupled gears. The synergistic activity of this system is fueled by the combined influence of biochemical signals and key biomechanical forces, specifically interstitial fluid flow, matrix stiffness, and oxygen gradients. While traditionalin vivomodels have elucidated foundational biological principles, they frequently fail to recapitulate the human-specific, multi-scale dynamics inherent to GBM pathology, thereby hindering translational progress. This review evaluates recent advancements in bioengineering strategies that transition beyond single-niche isolation toward a modular, 'niche-by-niche' reconstruction of the GBM TME. We highlight the evolving trajectory of microphysiological systems, where advanced 3D culture and biofabrication methods, such as organoids and bioprinted microfluidic constructs, are leveraged to incorporate multifaceted physicochemical cues in a highly controlled and reproducible manner. Furthermore, we address existing technical limitations and identify critical next steps in the field, including the integration of clinically relevant metrics and scalability. Finally, we propose that these engineered ecosystems serve as innovative tools for the advancement of precision oncology, providing a robust framework for tailoring therapeutic interventions to the unique profile of each patient.