Diagnostic biomarkers, prognostic signatures, and therapeutic resistance: shedding light on the dual role of autophagy in glioblastoma.

Glioblastoma (GBM) is an exceptionally aggressive brain malignancy with a dismal prognosis, characterized by a median survival of roughly 15 months despite standard radiotherapy and Temozolomide treatment. A primary driver of this therapeutic resistance is autophagy. While initially tumor-suppressive, autophagy transitions into a cytoprotective mechanism in established GBM, acting as a molecular survival switch that enables cells to withstand metabolic stress, hypoxia, and therapy-induced DNA damage. Crucially, this complex intracellular degradation process has emerged as a powerful tool for GBM diagnosis and prognosis. Autophagy-related genes (ARGs) are now established as highly sensitive diagnostic and prognostic biomarkers. Utilizing advanced bioinformatics, researchers have constructed robust prognostic risk models, such as 4-gene, 7-gene, and 10-lncRNA-mRNA signatures, that can accurately stratify patient risk, forecast tumor progression, and estimate overall survival. These molecular signatures provide vital diagnostic utility by distinguishing aggressive GBM phenotypes from lower-grade gliomas. Furthermore, these prognostic models strongly correlate with tumor microenvironment dynamics and immune infiltration, providing deep insights into immunosuppressive macrophage polarization. By profiling these autophagy-driven markers, clinicians can reliably anticipate chemoresistance and tailor personalized immunotherapy regimens. This review explores the signaling pathways regulating autophagy, the mechanisms driving radioresistance and chemoresistance, and the profound diagnostic and prognostic value of ARG signatures, highlighting emerging translational strategies to therapeutically target autophagy, overcome resistance, and improve clinical outcomes.