Interleukin‐37 in Cancer Angiogenesis: Mechanisms, Therapeutic Potential, and Future Perspectives

ABSTRACT Background Interleukin‐37 (IL‐37), a member of the interleukin‐1 family, is recognized as a key anti‐inflammatory cytokine that not only suppresses innate immune responses but also plays a significant role in regulating tumorigenesis, particularly angiogenesis. Mounting evidence indicates that IL‐37 shifts the balance between pro‐ and anti‐angiogenic factors toward anti‐angiogenic signaling by suppressing critical signaling pathways, including Signal transducer and activator of transcription 3 (STAT3), Akt/mTOR, Wnt/β‐catenin, and Notch. In breast, lung, colorectal, and hepatocellular cancers, reduced IL‐37 expression has been associated with higher tumor vessel density, more advanced disease stages, and poorer prognosis. Recent Findings In preclinical models, overexpression or administration of IL‐37 has led to decreased vascular endothelial growth factor (VEGF) levels, inhibition of hypoxia‐inducible factor‐1α (HIF‐1α), and enhanced expression of anti‐angiogenic factors, such as thrombospondin‐1 (TSP‐1). Clinically, low IL‐37 levels may serve as a potential biomarker for predicting survival and therapeutic response. Conclusion Despite promising findings, challenges remain, including optimizing delivery systems, managing the risk of immunosuppression, and conducting controlled clinical trials. IL‐37, predominantly produced by innate immune cells and detectable in the tumor and stromal compartments, exhibits therapeutic potential by modulating inflammatory and angiogenic signaling networks within the tumor microenvironment. A deeper understanding of IL‐37's molecular interactions with key pathways, along with the design of combination approaches, could pave the way for its practical clinical application.