Interleukin-37 in cancer: Context-dependent roles in tumor immunity, prognosis, and therapeutic targeting

Interleukin-37, a member of the interleukin-1 family, is increasingly recognized as a regulator of cancer biology and tumor immunity. Across cancer types, interleukin-37 expression exhibits divergent patterns and clinical associations. In non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, renal cell carcinoma, and acute myeloid leukemia, decreased interleukin-37 expression is more often associated with aggressive clinicopathologic features and poor outcomes. By contrast, in gastric cancer, epithelial ovarian cancer, melanoma, and several other malignancies, increased interleukin-37 expression has been linked to tumor progression and adverse prognosis. Mechanistically, interleukin-37 acts through intracellular and extracellular pathways, including Smad3-dependent nuclear translocation and signaling through the interleukin-18 receptor alpha/interleukin-1 receptor 8 complex, with downstream effects on signal transducer and activator of transcription 3, nuclear factor kappa B, transforming growth factor beta/Smad, and related networks. Depending on cancer type, immune context, isoform usage, and disease stage, interleukin-37 may inhibit proliferation, metabolic reprogramming, angiogenesis, invasion, and metastatic dissemination or promote immune suppression and premetastatic niche formation. Beyond its tumor-intrinsic effects, interleukin-37 reshapes the tumor microenvironment by modulating macrophages, dendritic cells, natural killer cells, myeloid-derived suppressor cells, and T-cell subsets. This narrative review summarizes current evidence on the dual roles of interleukin-37 in cancer, discusses major sources of inconsistency across studies, and highlights its potential relevance to prognostic stratification, biomarker development, and therapeutic targeting.