IFN-I signaling in cancer: the connection with dysregulated Insulin/IGF axis

• Published in: Trends in endocrinology and metabolism 2022-08, Vol.33 (8), p.569-586
• Main Authors: Vella, Veronica, De Francesco, Ernestina Marianna, Bonavita, Eduardo, Lappano, Rosamaria, Belfiore, Antonino
• Format: Article
• Language: English
• Subjects: IGF axis; insulin receptor isoform A; insulin receptor isoforms; interferon signaling
• ISSN: 1043-2760; 1879-3061
• DOI: 10.1016/j.tem.2022.04.009

Type I interferons (IFN-Is) are prototypical inflammatory cytokines produced in response to stress. IFN-Is have a critical role in antitumor immunity by driving the activation of leukocytes and favoring the elimination of malignant cells. However, IFN-I signaling in cancer, specifically in the tumor microenvironment (TME), can have opposing roles. Sustained IFN-I stimulation can promote immune exhaustion or enable tumor cell-intrinsic malignant features. Herein, we discuss the potential impact of the insulin/insulin-like growth factor system (I/IGFs) and of metabolic disorders in aberrant IFN-I signaling in cancer. We consider the possibility that targeting I/IGFs, especially in patients with cancer affected by metabolic disorders, contributes to an effective strategy to inhibit deleterious IFN-I signaling, thereby restoring sensitivity to various cancer therapies, including immunotherapy. In physiology, insulin/insulin-like growth factor system (I/IGFs) has a pivotal role in activating the immune system, including IFN-I signaling. Activation of the immune system induces insulin resistance by inhibiting glucose uptake in insulin target organs. Conversely, in cancer, both type I interferons (IFN-I) signaling and I/IGFs are dysregulated and may cooperate toward tumor progression.Dysregulated I/IGFs might help induce or maintain aberrant IFN-I signaling in malignant cells through the activation of the phosphoinositide 3-kinase (PI3K)/Akt and JAK/Stat pathways. Metabolic disorders may also promote IFN-I signaling in tumors through various mechanisms, including hyperinsulinemia, reactive oxygen species (ROS)-mediated DNA damage, and inflammatory signals from cancer-associated stromal cells.A full understanding of the complex relationship between IFN-I signaling in cancer and dysregulated I/IGFs may lead to the discovery of novel therapeutics against therapy-resistant and immune-evasive cancers.