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Review
. 2023 Sep 13;24(18):14026.
doi: 10.3390/ijms241814026.

Decoding the IL-33/ST2 Axis: Its Impact on the Immune Landscape of Breast Cancer

Bojan Stojanovic  1 , Nevena Gajovic  2 , Milena Jurisevic  3 , Milica Dimitrijevic Stojanovic  2   4 , Marina Jovanovic  5 , Ivan Jovanovic  2 , Bojana S Stojanovic  2   6 , Bojan Milosevic  1
Affiliations
Review

Decoding the IL-33/ST2 Axis: Its Impact on the Immune Landscape of Breast Cancer

Bojan Stojanovic et al. Int J Mol Sci. .

Abstract

Interleukin-33 (IL-33) has emerged as a critical cytokine in the regulation of the immune system, showing a pivotal role in the pathogenesis of various diseases including cancer. This review emphasizes the role of the IL-33/ST2 axis in breast cancer biology, its contribution to cancer progression and metastasis, its influence on the tumor microenvironment and cancer metabolism, and its potential as a therapeutic target. The IL-33/ST2 axis has been shown to have extensive pro-tumorigenic features in breast cancer, starting from tumor tissue proliferation and differentiation to modulating both cancer cells and anti-tumor immune response. It has also been linked to the resistance of cancer cells to conventional therapeutics. However, the role of IL-33 in cancer therapy remains controversial due to the conflicting effects of IL-33 in tumorigenesis and anti-tumor response. The possibility of targeting the IL-33/ST2 axis in tumor immunotherapy, or as an adjuvant in immune checkpoint blockade therapy, is discussed.

Keywords: Interleukin-33; breast cancer; immunotherapy; metastasis; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Primary structure of the human IL-33 protein. The protein structure is delineated into three principal domains: the N-terminal domain, which encompasses the nuclear localization signal and the chromatin binding site; the central domain, highlighting the cleavage sites for inflammatory proteases involved in IL-33 activation; and the C-terminal domain, characterized as the IL-1-like cytokine domain, with noted cleavage sites for caspases responsible for IL-33 inactivation.
Figure 2
Figure 2
IL-33/ST2 signaling cascade and associated outcomes in breast cancer. On the left side of the figure, the signaling cascade following the binding of IL-33 to the receptor complex is illustrated. Upon receptor activation, the intracellular signaling components, including MyD88, IRAK, ERK, and TRAF6, sequentially lead to the activation of NF-κB and MAPK pathways. On the right side of the figure, the outcomes of this signaling are depicted, including tumor growth and metastasis, immunosuppression, pro-angiogenic effects, and cancer cell dedifferentiation. Note: IL-33 (Interleukin-33), ST2L (Transmembrane ST2 receptor), sST2 (Soluble ST2), IL1RaCP (Interleukin-1 Receptor Accessory Protein), BCC (Breast Cancer Cell), BCSC (Breast Cancer Stem Cell), MyD88 (Myeloid Differentiation Primary Response 88), IRAK (Interleukin-1 Receptor-Associated Kinase), ERK (Extracellular Signal-Regulated Kinase), TRAF6 (TNF Receptor Associated Factor 6), AP-1 (Activator Protein 1), MAPK (Mitogen-Activated Protein Kinase), IKK (IκB Kinase), NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells), DNA (Deoxyribonucleic Acid), MDSCs (Myeloid-derived Suppressor Cells), Tregs (Regulatory T Cells), immDCs (Immature Dendritic Cells), and TILC (Tumor-infiltrating Innate Lymphoid Cells). The figure offers a comprehensive view of the IL-33/ST2 axis and how it contributes to various aspects of breast cancer pathogenesis.
Figure 3
Figure 3
Interplay of IL-33/ST2 Axis in breast carcinoma progression. Schematic representation illustrating the intricate interactions underpinning breast carcinoma progression. The central portrayal of an anomalous breast cancer cell emphasizes its principal interactions with surrounding molecules and cells. IL-33, emanating from the tumor, serves a pivotal role in modulating the tumor microenvironment and promotes the accumulation of immunosuppressive cells. Specifically, cells like Innate Lymphoid Cells 2 (ILC2) and T helper 2 (Th2) are attracted to the environment, underscoring their potential role in dampening the immune response against the tumor, which further bolsters tumor growth progression. In tandem, IL-33 is linked with a heightened expression of Vascular Endothelial Growth Factor (VEGF) molecules from the cancer cell, hinting at its role in fostering angiogenesis and boosting metastatic potential. The figure accentuates the multifaceted interplay and determinants shaping the progression of breast cancer.
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