The multifaceted role of cathepsin a in glioblastoma pathogenesis: from molecular scaffolding to immunological evasion.

Abstract

Glioblastoma (GBM) is a highly aggressive primary central nervous system malignancy characterized by pronounced intratumoral heterogeneity, rapid progression, and resistance to standard therapeutic approaches. Increasing evidence indicates that cathepsin A (CTSA), a lysosomal serine carboxypeptidase with multifunctional roles, is associated with aggressive GBM phenotypes and may contribute to tumor progression through multiple, context-dependent mechanisms. CTSA is an established structural component of the elastin receptor complex (ERC), where it stabilizes NEU1 and supports receptor complex integrity. Whether this scaffolding function facilitates matrikine-mediated signaling relevant to GBM invasion remains to be directly demonstrated. In parallel, CTSA participates in lysosomal regulatory pathways that may influence chaperone-mediated autophagy (CMA), a selective protein degradation process critical for maintaining cellular proteostasis under metabolic and oxidative stress conditions. However, the direct enzymatic action of CTSA on LAMP2A is expected to limit, rather than enhance, CMA activity, indicating that CTSA-high expression cannot be simply equated with CMA-high cellular states. Therefore, the relationships between CTSA expression, LAMP2A turnover, net CMA flux, and immune signaling in GBM remain unresolved. Dysregulation of lysosomal processes may influence protein turnover and stress-adaptive pathways in GBM; however, the specific contribution of CTSA to these processes has not yet been experimentally tested. CTSA-associated lysosomal activity has been linked to the modulation of the tumor immune microenvironment. CTSA-related signatures are associated with increased representation of immunosuppressive myeloid populations, along with reduced effector immune activity, suggesting that CTSA may serve as a marker of immune-suppressed GBM states rather than as a proven causal regulator of immune exclusion. Consistent with this, CTSA-associated changes in lysosomal function may influence immune-related signaling pathways in a context-dependent manner. At the transcriptomic level, CTSA-linked gene expression patterns, including the SLC39A1-CTSA-CLIC1 axis, are associated with mesenchymal-like states and may serve as candidate prognostic indicators in glioma. Thus, CTSA-associated lysosomal pathways provide a hypothesis-generating framework for exploring lysosome-centered vulnerabilities in GBM; although direct functional and translational validation is still needed, CTSA is best interpreted not as a validated oncogenic driver but as a lens for aggressive, mesenchymal-like and myeloid-enriched glioma states and for interpreting lysosome/CMA-associated vulnerabilities.