Unfolded Protein Response in Glioblastoma: Mechanisms of Proteostasis, Tumor Adaptation, and Therapeutic Relevance

Glioblastoma (GBM) is an aggressive brain tumor that rapidly develops resistance to standard clinical therapies. The tumor microenvironment of GBM is highly hostile, characterized by hypoxia, elevated reactive oxygen species, and severe metabolic stress. These conditions promote protein misfolding, particularly in the endoplasmic reticulum (ER), thereby triggering ER stress. The unfolded protein response (UPR) is an adaptive signaling pathway that mitigates ER stress, restores proteostasis, and promotes cellular survival. Activation of UPR signaling provides a survival advantage to GBM cells under these adverse conditions. This signaling is closely associated with drug resistance and malignant progression in GBM. Furthermore, inhibition of UPR sensors exhibits anticancer effects, highlighting their potential as therapeutic targets in GBM. This review describes the biological functions of UPR sensors and their roles in GBM pathogenesis and treatment response.