Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenviron-ments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we activated the ISR using salubrinal in cancer cells and found that salubrinal repressed cell growth, colony formation, and migration but did not induce cell death in a glucose-containing condition. Under a glucose-deprivation condition, salubrinal induced cell death and increased the levels of mitochondrial reactive oxygen species (ROS). We found that these effects of salubrinal and glucose deprivation were associated with the upregulation of xCT (SLC7A11), which functions as an antiporter of cystine and glutamate and maintains the level of glutathione to maintain redox homeostasis. The upregulation of xCT did not protect cells from oxidative stress-mediated cell death but promoted it during glucose deprivation. In addition, the supplementation of ROS scavenger N-acetylcysteine and the maintenance of intracellular levels of amino acids via sulfasalazine (xCT inhibitor) or dimethyl-α-ketoglutarate decreased the levels of mitochondrial ROS and protected cells from death. Our results suggested that salubrinal enhances cancer cell death during glucose deprivation through the upregulation of xCT and mitochondrial oxidative stress.