IL-37/IL-1R8 axis: a novel major mechanism of control at the interface between tumor and immune cells

Interleukin (IL)-37 is one of the "youngest" IL-1 family members and one of the few molecules exerting anti-inflammatory activity. Upon inflammasome activation, the cytokine precursor is converted into its mature form, which acts intracellularly as a nuclear transcription factor, impairing the production of pro-inflammatory cytokines, and extracellularly by forming the IL-37/IL-18Rα/IL-1R8 complex, favoring IL-1R8 inhibitory signaling with immunosuppressive function. IL-1R8, which is mostly expressed in a number of cell types, negatively regulates both IL-1R/TLR signaling, blocking the NF-kB/JNK pathway and the production of pro-inflammatory cytokines. Owing to its ability to inhibit both innate and adaptive immunity, IL-37 has been reported to control inflammation in many chronic disorders, including cancer. IL-37 impairs the proliferation and migration of tumor cells, mediates anti-angiogenetic mechanisms, and favors immunoregulation in the tumor microenvironment (TME). This review aims to provide a current overview of IL-37 genetic and biological features and of its active interaction with IL-1R8, inducing anti-inflammatory effects on the immune system and affecting cancer cell dynamics in the TME. Moreover, it analyzes the rare pro-tumoral effects of IL-37 in some tumors and discusses their possible mechanisms. It concludes that, due to its strong anti-inflammatory property, IL-37 can be considered a potential regulator in the pathogenesis of a variety of cancers, slowing tumor progression through multiple pathways and providing valuable information for tumor immune target therapy.