Interleukin-33: A new frontier in cancer immunotherapy

Interleukin (IL)-33 is a member of the IL-1 cytokine family that is involved in critical physiological functions. IL-33 is constitutively expressed in the nucleus of many cell types and participates in gene regulation. However, during inflammation, IL-33 is released by cells to promote an immune response and favor tissue repair. Often referred to as an 'alarmin' due to its involvement in the early stages of inflammation, IL-33 binds to its receptor ST2 and directly modulates the activity of various immune and non-immune cell subsets. The role of the IL-33/ST2 axis has been extensively studied in reference to various inflammatory diseases and allergic responses. In cancer, this axis plays a dual role, driving pro-tumorigenic and anti-tumorigenic responses depending on the cancer type, disease stage and tumor microenvironment composition. These observations highlight the pleiotropic role exhibited by this axis in tumors. Efforts are currently being made to better understand its underlying mechanisms with the aim to exploit its therapeutic potential, alone or in combination with other anti-cancer immunotherapies. In this review, we discuss the physiological relevance of IL-33 in the context of inflammation, tumor development and progression, its impact on the tumor microenvironment, and its future application in cancer immunotherapy. Advanced understanding of the knowledge gaps and nuances pertaining to the IL-33/ST2 axis will enable the formulation of better treatments to improve patient outcomes.