The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting

Cancer cells face continual stressors, which they must overcome to proliferate and survive in the body. Under these conditions, essential biochemical pathways are disrupted, contributing to various stress responses that either promote adaptation and survival or eventual cell death. The evolutionarily conserved integrated stress response (ISR) is a key adaptive mechanism that transiently rewires the transcriptome and translatome in response to various stressors. While the ISR is activated in healthy cells under moderate stress, cancers especially rely on this pathway to overcome harsh conditions experienced during tumor growth and metastasis. We explore the pro-tumorigenic role of the ISR, along with the upstream stress-sensing kinases that activate it. These include protein kinase R-like endoplasmic reticulum kinase, general control non-derepressible 2, double-stranded RNA-dependent protein kinase, and heme-regulated eukaryotic translation initiation factor 2α kinase (HRI), which initiate an ISR in response to diverse stressors by phosphorylating their shared substrate, eukaryotic initiation factor-2α. An in-depth understanding of the pro-survival functions of the ISR and the contexts in which it is pro-tumorigenic is necessary to leverage the ISR as a therapeutic strategy.