Understanding the unfolded protein response in glioblastoma

Glioblastoma is the most aggressive and lethal malignancy of the central nervous system and exhibits a complex interplay with endoplasmic reticulum (ER) stress (ERS). The multifunctional ER is the primary site of the unfolded protein response (UPR), which is activated under conditions of ERS to enhance protein-folding capacity and promote cell survival. However, persistent ERS can trigger apoptosis. Despite extensive research over the past decades, the mechanistic insights into the impact of ERS and the UPR on glioblastoma pathogenesis and progression remain unclear. The UPR operates through three canonical signaling pathways: inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK, also known as EIF2AK3) and activating transcription factor 6 (ATF6). These pathways regulate glioblastoma development through both independent and synergistic mechanisms. In this Review, we discuss the current state of research on the role of the UPR in glioblastoma and delineate the distinct mechanisms of each signaling pathway. Furthermore, we evaluate the challenges associated with UPR-targeting therapeutic agents and propose possible treatment strategies to leverage the regulatory mechanisms of the different UPR pathways to overcome these limitations.