The Extracellular Matrix, the Silent 'Architect' of Glioma

The brain's extracellular matrix (ECM) serves as a dynamic and instructive regulator of glioma progression. The ECM provides structural support while integrating pharmacological and mechanical signals that influence glioma initiation, progression, and treatment resistance. Deviant ECM remodeling fosters tumor heterogeneity, invasion, and immune evasion by altering stiffness, composition, and cellular matrix signaling. We proposed that ECM remodeling in gliomas not only facilitates tumor growth and heterogeneity but also establishes advantageous biophysical and metabolic conditions that foster treatment resistance and recurrence. Our objective is to analyze current findings regarding the structural, biochemical, and mechanical roles of the brain ECM in glioma growth, emphasizing its contribution to tumor heterogeneity, mechanotransduction, immunological modulation, and its potential as a therapeutic target.

A comprehensive literature review was conducted using scientific databases including PubMed, Web of Science, and Scopus. Peer-reviewed literature published between 2000 and 2025 was selected for its relevance to ECM composition, stiffness, remodeling enzymes, extracellular vesicles, and mechanobiological processes in gliomas.

Recent investigations demonstrate that glioma cells actively alter the ECM by secreting collagens, laminins, and metalloproteinases, establishing a feedback loop that facilitates invasion and resistance.

Mechanical variables, such as ECM stiffness and solid stress, influence glioma growth, metabolism, and immune exclusion. Moreover, extracellular vesicles facilitate significant extracellular matrix remodeling and improve communication between tumors and stromal cells. The disruption of ependymal and subventricular extracellular matrix niches enhances invasion and cerebrospinal fluid-mediated signaling. The remodeling of the ECM influences glioma growth through interconnected biochemical, mechanical, and immunological mechanisms. Examining ECM stiffness, crosslinking enzymes, and vesicle-mediated signaling represents a potential therapeutic approach. Integrative methodologies that combine mechanobiology, imaging, and multiomics analysis could uncover ECM-related vulnerabilities to improve glioma treatment.