A wide range of stressors in the tumor microenvironment can trigger the integrated stress response (ISR) that is mediated by four sensors: general control nonderepressible (GCN2) that detects amino acid depletion, protein kinase R (PKR) that recognizes viral double-stranded RNA, heme-regulated inhibitor (HRI) that is induced by heme deficiency, and PKR-like endoplasmic reticulum kinase (PERK) that detects ER stress. Here, EIF2AK2 is linked to neoplasm.