Abstract
Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with therapy resistance significantly hindering treatment efficacy. This review explores the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in NSCLC progression and resistance mechanisms. Under stress conditions such as hypoxia, nutrient deprivation, or therapeutic insult, the UPR balances adaptive survival signaling and apoptotic pathways. Key UPR sensors-PERK, IRE1α, and ATF6-are dysregulated in NSCLC, enabling tumor cells to evade death despite microenvironmental or treatment-induced stress. Preclinical studies highlight therapeutic strategies targeting ER stress through reactive oxygen species (ROS) induction, calcium homeostasis disruption, and proteasome inhibition, which shift the UPR toward pro-apoptotic outcomes. Agents such as proteasome inhibitors, natural compounds, and repurposed drugs demonstrate the potential to overcome resistance by enhancing chemosensitivity, reversing chemoresistance, and improving radiosensitivity. Combination therapies synergize ER stress inducers with conventional treatments, leveraging immunogenic cell death (ICD) to augment anti-tumor immunity. However, challenges persist due to the UPR's context-dependent outputs and the gap between preclinical models and clinical applicability. Future directions include optimizing combination regimens, identifying predictive biomarkers, and advancing personalized approaches. Translating these insights into clinical trials is critical to validate ER stress modulation as a viable strategy for improving NSCLC outcomes, offering a promising avenue to address unmet needs in this aggressive malignancy.