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

Sep 23, 2026

Interleukin-37 (IL-37), an interleukin-1 family anti-inflammatory cytokine, suppresses innate immune activation while regulating tumorigenesis, especially angiogenesis. Evidence indicates IL-37 shifts pro-angiogenic and anti-angiogenic factor balance toward anti-angiogenic signaling by inhibiting pathways including STAT3, Akt/mTOR, Wnt/β-catenin, and Notch. Reduced IL-37 expression correlates with higher vessel density, advanced cancer stages, and worse outcomes. Preclinical studies show IL-37 lowers VEGF, suppresses HIF-1α, and increases anti-angiogenic mediators such as TSP-1; low IL-37 may inform biomarker use.

LanguageEnglish

CategoryHealthcare

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Pages13

Reading Time33 min

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Abstract

Introduction

IL-37 structure, variants, and expression

IL-37 and immune regulation

IL-37 intracellular and extracellular actions

Angiogenesis in cancer

Cancer Reports REVIEW OPEN ACCESS Interleukin-37 in Cancer Angiogenesis: Mechanisms, Therapeutic Potential, and Future Perspectives Elahe Saberi Teimourian1 | Mohammad Ali Karimi2 | Edessa Negera1 | Ghazaleh Behrouzian Fard2 | Anas Sattar1 | Mahdi Hosseini Bafghi2 | Nirusha Weerasinghe1 1School of Health, Sports and Biosciences, University of East London, London, UK | 2Department of Laboratory Sciences, Faculty of Paramedical and Rehabilitation Sciences, Mashhad University of Medical Sciences, Mashhad, Iran Correspondence: Mahdi Hosseini Bafghi ([m_hosseini79@yahoo.com](m_hosseini79@yahoo.com)) | Nirusha Weerasinghe ([n.weerasinghe@uel.ac.uk](n.weerasinghe@uel.ac.uk)) Received: 13 November 2025 | Revised: 4 May 2026 | Accepted: 11 May 2026 Keywords: angiogenesis | cytokine-based therapy | Interleukin-37 | tumor immunology | tumor microenvironment 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 antiangiogenic 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. 1 | Introduction Interleukin-37 (IL-37), a prominent member of the interleukin-1 family, was first identified and characterized in 2000. The IL- 37-encoding gene is located within a gene cluster near IL-18 and IL-1β on human chromosome 2 and shares structural and functional homology with these genes [1] . To date, five splice variants of IL-37 have been identified (IL-37a–e), among which the IL-37b isoform has been the most extensively studied in functional analyses [2]. Initially recognized for its anti-inflammatory properties, IL-37 was established as a negative regulator of innate immune responses. Evidence demonstrates that this cytokine can suppress the production of proinflammatory cytokines and attenuate inflammation across various disease models [3] . Given the absence of a murine ortholog for IL-37, its functional studies are conducted in transgenic models expressing human IL-37 [4]. IL-37 expression is inducible and present at low levels under physiological conditions, but is significantly upregulated by inflammatory stimuli such as lipopolysaccharide (LPS), IL- 1β, and TNF-α [5] . | Elahe Saberi Teimourian and Mohammad Ali Karimi contributed equally to this manuscript. | | --- | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any m

FAQs

How does IL-37 influence cancer angiogenesis?

IL-37 suppresses pro-angiogenic signaling by downregulating key pathways (including STAT3, Akt/mTOR, Wnt/β-catenin, and Notch), which helps shift the balance toward anti-angiogenic factors.

What preclinical effects have been reported after IL-37 overexpression or administration?

Preclinical models show decreased VEGF levels, inhibition of HIF-1α, and increased expression of anti-angiogenic mediators such as thrombospondin-1 (TSP-1).

What challenges limit translating IL-37 into clinical therapy?

The document highlights the need to optimize delivery systems, manage immunosuppression risk, and conduct controlled clinical trials to establish clinical utility.

Sep 23, 2026

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