Agree to disagree: The contradiction between IL-18 and IL-37 reveals shared targets in cancer

IL -37 is a newly discovered member of the IL -1 cytokine family which plays an important role in regulating inflammation and maintaining physiological homeostasis. IL -37 showed a close relationship with IL -18, another key cytokine in inflammation regulation and cancer development. IL -37 affects the function of IL -18 either by binding to IL-18R alpha, a key subunit of both IL -37 and IL -18 receptor, or by drastically neutralizing the IL -18 protein expression of IL -18 binding protein, an important natural inhibitory molecule of IL -18. Moreover, as another subunit receptor of IL -37, IL -1R8 can suppress IL-18R alpha expression, functioning as a surveillance mechanism to prevent overactivation of both IL -18 and IL -37 signaling pathways. While IL -18 and IL -37 share the same receptor subunit, IL -18 would in turn interfere with IL -37 signal transduction by binding to IL-18R alpha. It is also reported that IL -18 and IL -37 demonstrated opposing effects in a variety of cancers, such as glioblastoma, lung cancer, leukemia, and hepatocellular cancer. Although the mutual regulation of IL -18 and IL -37 and their diametrically opposed effects in cancers has been reported, IL -18 has not been taken into consideration when interpreting clinical findings and conducting mechanism investigations related to IL -37 in cancer. We aim to review the recent progress in IL -18 and IL -37 research in cancer and summarize the correlation between IL -18 and IL -37 in cancer based on their expression level and underlying mechanisms, which would provide new insights into elucidating the conflicting roles of IL -18 and IL -37 in cancer and bring new ideas for translational research related to IL -18 and IL -37.