Mortality rates related to non-small-cell lung cancer (NSCLC) remain still high, with about 75% of patients getting little clinical benefit from therapy. Adverse conditions in the tumor microenvironment, such as hypoxia or oxidative stress, disrupt the protein-folding capacity of the endoplasmic reticulum (ER) in infiltrating cells, provoking cellular stress that activates the unfolded protein response (UPR) pathway to restore proteostasis in this cellular organelle. During ER stress, serine/threonine-protein kinase/endoribonuclease IRE1 exerts its endoribonuclease activity on XBP1 mRNA generating a splice variant that encodes XBP1s that induces UPR target gene expression.