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

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.

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.

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.