Ghemrawi Rose, Kremesh Sedra, Mousa Walaa K, Khair Mostafa
College of Pharmacy, Al Ain University, Abu Dhabi, United Arab Emirates;
AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi, United Arab Emirates.
Cancer Genomics Proteomics. 2025 May-Jun;22(3):363-381. doi: 10.21873/cgp.20507.
Dysregulation of protein synthesis, folding, and secretion leads to endoplasmic reticulum (ER) stress, triggering the unfolded protein response (UPR). While the UPR is essential for cell survival under stress, its chronic activation in cancer cells supports tumorigenesis, metastasis, and chemoresistance by enabling cellular adaptation to hypoxia, nutrient deprivation, and oxidative stress. This review provides a comprehensive overview of the roles of key UPR mediators - binding immunoglobulin protein (BiP), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) - in cancer progression and therapy resistance. Furthermore, it discusses strategies to target UPR pathways, including small molecule inhibitors, gene therapies, natural compounds, and combination therapies, while it evaluates their preclinical and clinical relevance. Finally, it explores how modulating UPR signaling can overcome therapeutic resistance, improve immunotherapy outcomes, and reshape the tumor microenvironment. This review emphasizes the promise of UPR-targeted approaches in enhancing the efficacy of current cancer treatments and achieving better patient outcomes.
蛋白质合成、折叠和分泌的失调会导致内质网（ER）应激，从而触发未折叠蛋白反应（UPR）。虽然UPR对于应激条件下的细胞存活至关重要，但它在癌细胞中的长期激活通过使细胞适应缺氧、营养剥夺和氧化应激来支持肿瘤发生、转移和化疗耐药性。本综述全面概述了关键UPR介质——结合免疫球蛋白蛋白（BiP）、蛋白激酶R（PKR）样内质网激酶（PERK）、肌醇需求酶1α（IRE1α）和激活转录因子6（ATF6）——在癌症进展和治疗耐药性中的作用。此外，它还讨论了靶向UPR途径的策略，包括小分子抑制剂、基因疗法、天然化合物和联合疗法，同时评估了它们的临床前和临床相关性。最后，它探讨了调节UPR信号如何克服治疗耐药性、改善免疫治疗结果以及重塑肿瘤微环境。本综述强调了靶向UPR方法在提高当前癌症治疗疗效和实现更好患者预后方面的前景。
