The complex roles of IL-36 and IL-38 in cancer: friends or foes?

Abstract The interleukin-36 (IL-36) family comprises of three pro-inflammatory receptor agonists (IL-36α, IL-36β and IL-36γ), two anti-inflammatory receptor antagonists (IL-36RA and IL-38) along with the IL-36 receptor (IL-36R). Part of the IL-1 cytokine superfamily, the IL-36 family was discovered in the early 2000s due to the homology of its member sequences to the IL-1 cytokines. As pro- and anti-inflammatory cytokines, respectively, IL-36α, IL-36β, IL-36γ and IL-38 aid in maintaining homoeostasis by reciprocally regulating the body’s response to damage and disease through IL-36R-associated signalling. With the significant roles of IL-36α, IL-36β and IL-36γ in regulating the immune response realised, interest has grown in investigating their roles in cancer. While initial studies indicated solely tumour-suppressing roles, more recent work has identified tumour-promoting roles in cancer, suggesting a more complex dual functionality of the IL-36 cytokines. The activity of IL-38 in cancer is similarly complex, with the receptor antagonist displaying distinct tumour-suppressive roles, particularly in colorectal cancer (CRC), in addition to broad tumour-promoting roles in various other malignancies. This review provides a comprehensive overview of the IL-36 and IL-38 cytokines, their activation and IL-36R signalling, the physiological functions of these cytokines, and their activity in cancer.