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Nevena Gajovic 2,†, Milena Jurisevic 3, Milica Dimitrijevic Stojanovic 2,4,*, Marina Jovanovic 5, Ivan Jovanovic 2, Bojana S. Stojanovic 2,6,* and Bojan Milosevic 1  \nCitation: Stojanovic, B.; Gajovic, N.; Jurisevic, M.; Stojanovic, M.D.; Jovanovic, M.; Jovanovic, I.;  \nStojanovic, B.S.; Milosevic, B. Decoding the IL-33/ST2 Axis: Its Impact on the Immune Landscape of Breast Cancer. Int. J. Mol. Sci. 2023, 24, 14026. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms241814026](10.3390/ijms241814026)  \nAcademic Editor: Yasuhiro Miki  \n1 Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; [bojan.stojanovic01@gmail.com](bojan.stojanovic01@gmail.com) (B.S.)  \n2 Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; [ivanjovanovic77@gmail.com](ivanjovanovic77@gmail.com) (I.J.)  \n3 Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; [milena.jurisevic13@gmail.com](milena.jurisevic13@gmail.com)  \n4 Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia  \n5 Department of Otorinolaringology, Faculty of Medical Sciences, University of Kragujevac,  \n34000 Kragujevac, Serbia  \n6 Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac,  \n34000 Kragujevac, Serbia  \n* [Correspondence: milicadimitrijevic@yahoo.om](Correspondence: milicadimitrijevic@yahoo.om) (M.D.S.); [bojana.stojanovic04@gmail.com](bojana.stojanovic04@gmail.com) (B.S.S.)† These authors contributed equally to this work.  \nAbstract: 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.  \nKeywords: Interleukin-33; breast cancer; tumor microenvironment; immunotherapy; metastasis  \n1. Introduction  \nReceived: 10 August 2023  \nRevised: 1 September 2023  \nAccepted: 7 September 2023  \nPublished: 13 September 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \nBreast cancer, characterized by an uncontrolled proliferation of mammary gland cells, is the most frequently diagnosed malignancy in women globally [1] . With an estimated 2.2 million cases and approximately 700,000 fatalities in 2021, there is an indisputable urgency to advance early detection techniques, innovate therapeutic interventions, and extend the realm of research [1] . These alarming statistics underscore the profound need for progress towards the effective management and, ultimately, the eradication of this substantial global health burden.  \nComprising approximately 14","cbCairo3mQyfNN0w","https://ap.wps.com/l/cbCairo3mQyfNN0w","pdf",2884071,"English","# Abstract\n# Introduction\n## Breast cancer burden and need for improved management\n## Metastasis as the main driver of mortality\n## Heterogeneity and molecular subtypes\n## IL-33 biology and relevance to cancer","[{\"question\":\"What biological processes does the IL-33/ST2 axis affect in breast cancer?\",\"answer\":\"The review emphasizes effects on cancer progression and metastasis, including tumor cell proliferation and differentiation, modulation of the tumor microenvironment, and impacts on cancer metabolism.\"},{\"question\":\"How is IL-33 linked to treatment resistance in breast cancer?\",\"answer\":\"The IL-33/ST2 axis is reported as being associated with resistance of cancer cells to conventional therapeutics.\"},{\"question\":\"Why is targeting IL-33/ST2 considered controversial in cancer therapy?\",\"answer\":\"Because IL-33 is described as having conflicting effects across tumorigenesis and anti-tumor immune responses, the therapeutic role in cancer treatment remains debated.\"}]","Decoding the IL-33/ST2 Axis: Its Impact on the Immune Landscape of Breast Cancer | PDF",1790229152]