IL‐36γ and IL‐36Ra Reciprocally Regulate NSCLC Progression by Modulating GSH Homeostasis and Oxidative Stress‐Induced Cell Death

The balance between antioxidants and reactive oxygen species (ROS) critically regulates tumor initiation and progression. However, whether and how the tumor‐favoring redox status is controlled by cytokine networks remain poorly defined. Here, it is shown that IL‐36γ and IL‐36Ra reciprocally regulate the progression of non‐small cell lung cancer (NSCLC) by modulating glutathione metabolism and ROS resolution. Knockout, inhibition, or neutralization of IL‐36γ significantly inhibits NSCLC progression and prolongs survival of the Kras (LSL‐G12D/+) Tp53 (fl/fl) and Kras (LSL‐G12D/+) Lkb1 (fl/fl) mice after tumor induction, whereas knockout of IL‐36Ra exacerbates tumorigenesis in these NSCLC mouse models and accelerates death of mice. Mechanistically, IL‐36γ directly upregulates an array of genes involved in glutathione homeostasis to reduce ROS and prevent oxidative stress‐induced cell death, which is mitigated by IL‐36Ra or IL‐36γ neutralizing antibody. Consistently, IL‐36γ staining is positively and negatively correlated with glutathione biosynthesis and ROS in human NSCLC tumor biopsies, respectively. These findings highlight essential roles of cytokine networks in redox for tumorigenesis and provide potential therapeutic strategy for NSCLC.