To promote or inhibit glioma progression, that is the question for IL-33.

IL-33, a member of the IL-1 cytokine family has been shown to play a dual role within the body. First IL-33, similar to other IL-1 family members, is a secreted cytokine that binds to the cell surface receptor ST2 to induce a number of cell signaling pathways. Second, IL-33 enters the nucleus where it binds chromatin and directs transcriptional control of an array of growth factors and cytokines. Consistent with its complex cellular regulation, IL-33 mediates an array of biological functions by acting on a wide range of innate and adaptive immune cells. Recently, we found that IL-33 is expressed in a large number of human glioma patient specimens where its expression within the tumor correlates with the increased presence of Iba+ cells that include both resident microglia and recruited monocyte and macrophages. Strikingly, glioma derived expression of IL-33 correlates with a dramatic decrease in overall survival of tumor-bearing animals and thus supports its role as an influential factor in gliomagenesis. Notably however, when the nuclear localization function of IL-33 is crippled, the tumor microenvironment is programmed to be anti-tumorigenic and results in prolonged overall survival suggesting that when educated appropriately this could represent a novel therapeutic strategy for glioma (De Boeck (2020), Nat Commun, doi: 10.1038/s41467-020-18569-4).