The promising role of cathepsins as biomarkers and therapeutic targets in glioblastoma

Glioblastoma (GB) is the most aggressive and lethal primary brain tumor in adults, characterized by extensive intratumoral heterogeneity, high invasiveness, and resistance to standard therapies. Despite advances in surgical techniques and combined radio-chemotherapy, patient prognosis remains poor, highlighting the urgent need for reliable biomarkers and novel therapeutic targets. In this context, increasing evidence supports a critical role for cathepsins, a family of lysosomal proteases, in GB pathophysiology. Cathepsins are involved in multiple biological processes relevant to tumor progression, including extracellular matrix remodeling, invasion, angiogenesis, immune modulation, and regulation of cell death. Several cathepsin subtypes exhibit dysregulated expression and activity in GB tissues and patient-derived samples, correlating with tumor grade, aggressiveness, and clinical outcomes. These features position cathepsins as attractive candidates for both biomarker development and therapeutic targeting. This review provides a comprehensive overview of current knowledge on the role of cathepsins in GB biology. We summarize evidence from preclinical and clinical studies describing their contribution to tumor growth and invasion, their interaction with the tumor microenvironment, and their relevance in the context of treatment resistance. Furthermore, we discuss emerging strategies aimed at targeting cathepsins. Finally, we address current limitations and unresolved questions, outlining the future research directions needed to translate cathepsin-based biomarkers and therapies into clinical practice.