When the Matrix Warns: Unraveling Brain Extracellular Matrix Components as Danger Signals in Glioma Progression

The brain constitutes a biologically unique environment tasked with executing the most sophisticated functions of information processing and storage. This singularity arises from several factors, including its status as an immunoprivileged organ. Moreover, the brain extracellular matrix (ECM) provides a structural scaffold for cells and simultaneously acts as an active mediator for information storage and transmission. Unsurprisingly, the ECM has become firmly embedded as a key component of the tetrapartite synapse concept, which has gathered considerable traction in recent decades. In the present review, we aim to characterize the principal ECM components in the context of normal physiology, pathology, and damage-associated molecular patterns (DAMPs). Understanding this perspective is key to neurooncological progression, since the brain’s immune responses remain distinct even when the blood–brain barrier is compromised. A detailed examination of individual ECM constituents offers valuable insight into the mechanisms of tumor-driven microenvironment remodeling. Thus, these molecules should be considered not merely surrogate markers, but rather active drivers of key pathological processes in the central nervous system (CNS). Herein, we summarize and systematize the current evidence on extracellular DAMPs, paying special attention to their relevance in the brain. Our analysis focuses on ECM components that are abundant and functionally significant in the CNS, including the small leucine-rich proteoglycans (decorin, biglycan, and asporin), heparan sulfate proteoglycans, as well as tenascin C, versican, and hyaluronic acid.