The Unfolded Protein Response—Novel Mechanisms, Challenges, and Key Considerations for Therapeutic Intervention

BACKGROUND: The unfolded protein response (UPR) is an evolutionarily conserved, synchronized, and orchestrated process triggered by eukaryotic cells in response to endoplasmic reticulum (ER) stress. UPR restores the ER's capacity to handle large protein loads within it, and still fold and process these proteins accurately. Many recent studies have documented the non-canonical roles of the UPR, outside of protein quality control, in the context of lipid metabolism and the immune system in cancer. Cancer cells have been known to hijack the UPR to promote survival and evade immune surveillance. However, the underlying mechanisms remain poorly understood. OBJECTIVES: Here, we critically summarize canonical and non-canonical UPR mechanisms in the contexts of tumor immune microenvironment and lipid metabolism, dissect their crosstalk with other cell fate signaling pathways within cancer, and propose therapeutic strategies to exploit this relationship. We also discuss the fundamental challenges of solely targeting UPR and emphasize the importance of patient stratification, biomarker development, and rational combination therapies to maximize the potential for therapeutic gain. We provide a deconvoluted mechanistic understanding of the UPR process in an attempt to spark prospective clinically relevant therapeutics research.