IRE1α-mediated UPR activation in gastrointestinal cancers: adaptive mechanisms and therapeutic potential.

The endoplasmic reticulum (ER) plays a crucial part in protein synthesis, folding and quality control. Disruptions in these processes lead to ER stress (ERS) and activate the unfolded protein response (UPR) to restore cellular homeostasis. In gastrointestinal cancers, inositol-requiring enzyme 1α (IRE1α) is a key regulator of the UPR, helping cancer cells adapt to hostile conditions such as hypoxia, oxidative stress and chemotherapy. Elevated IRE1α activity supports tumor survival, progression and metastasis by mitigating ERS-induced apoptosis. However, targeting IRE1α signaling presents a promising therapeutic strategy, potentially impairing cancer cell adaptation to stress and enhancing treatment efficacy. Targeting IRE1α offers promising therapeutic opportunities for gastrointestinal cancer.