The hidden hand of endoplasmic reticulum stress in anticancer drug resistance.

Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) play pivotal roles in cancer adaptation and drug resistance. Under stress, dissociation of BiP from ER stress sensors activates three pathways such as PERK, IRE1α, and ATF6, which together promotes tumor cell survival. The PERK-eIF2α-ATF4 axis also suppresses global protein synthesis by inhibiting cyclin D, induces G1 arrest, and selectively enhances pro-survival gene translation. Simultaneously, IRE1α splices XBP1 mRNA to generate XBP1s, augmenting chaperone production, endoplasmic-reticulum-associated degradation (ERAD), and antioxidant defenses, while its RIDD activity selectively degrades mRNAs to alleviate proteotoxic stress. Concurrently, ATF6 traffics to the Golgi, where S1P/S2P cleavage releases ATF6-p50, a transcriptional activator of chaperones and anti-apoptotic genes. Collectively, these adaptive UPR mechanisms enable cancer cell survival, metastasis, and therapeutic resistance under proteotoxic and treatment-induced stress. Therapeutically, targeting the UPR offers dual potential; either inhibiting its pro-survival arms using selective small-molecule inhibitors (e.g., GSK2606414 for PERK, MKC-3946 for IRE1α) or exacerbating ER stress beyond the adaptive threshold to trigger apoptosis. This review critically evaluates how ERS-UPR signaling fosters tumor resilience across diverse malignancies, including breast, prostate, colorectal, and pancreatic cancers, and underscores the need to exploit UPR modulation as a strategy to resensitize tumors to conventional and targeted therapies.