Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.

Endoplasmic reticulum (ER) is a multifunctional organelle essential for maintaining proteostasis, lipid and carbohydrate metabolism, and calcium homoestasis. Rapidly dividing cancer cells driven by oncogenes, elevated translational output, increased metabolic demands, and a hostile tissue microenvironment overwhelm the protein-folding machinery of ER, leading to massive accumulation of unfolded proteins within the ER's lumen leading to chronic ER stress. This activates the unfolded protein response (UPR), a conserved signaling network mediated by three principal sensors: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1-alpha (IRE1α), and activating transcription factor 6 (ATF6), which functions to restore proteostasis or induce apoptosis under unresolved ER stress. Accumulating evidence indicates that malignant cells hijack the pro-adaptive function of the UPR pathway not only to thrive but also to promote cancer progression by invasion and metastasis. UPR activation modulates transcriptional and translational programs that contribute to angiogenesis, invasion, metastasis, immune escape, and chemoresistance. In this review, we dissect how cells balance this tightrope between adaptation and cell death in the context of cancer. We also explore how UPR signaling drives angiogenesis, metastasis, immune-evasion, and chemoresistance before finally discussing its therapeutic potential.