The differential role of IL-33 and IL-38 in prostate cancer - contradictory roles

Sep 23, 2026

Minireview analyzes how IL-33 and IL-38 shape the prostate cancer tumor microenvironment and influence host immune surveillance. Intra-tumoral IL-33 is reduced in cancer, correlating with aggressive features, including higher Gleason scores and lymphatic metastasis, and may protect through ST2/NF-kB signaling and lymphocyte recruitment. In contrast, intra-tumoral IL-38 is elevated, associates with tumor severity, advanced TNM stage, and worse overall survival, and may promote immunosuppression by limiting CD8+ infiltration and enhancing Tregs. Patterns suggest biomarker potential and motivate multi-center and functional studies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages5

Reading Time13 min

AccessFree to download

Introduction

Host immunity and prostate cancer

TYPE Mini Review PUBLISHED 18 June 2025 DOI 10.3389/fimmu.2025.1623038 OPEN ACCESS EDITED BY Tiezheng Hou, University College London, United Kingdom REVIEWED BY Qihan Dong, Macquarie University, Australia *CORRESPONDENCE Bin Zhou [zhoubin771122@163.com](zhoubin771122@163.com)[ ](zhoubin771122@163.com)Shisan Bao [profbao@hotmail.com](profbao@hotmail.com) †These authors have contributed equally to this work and share ﬁrst authorship RECEIVED 05 May 2025 ACCEPTED 09 June 2025 PUBLISHED 18 June 2025 CITATION Ban R, Gao S, Zhou B and Bao S (2025) The differential role of IL-33 and IL-38 in prostate cancer, contradictory roles. Front. Immunol. 16:1623038 . doi: 10.3389/fimmu.2025.1623038 COPYRIGHT © 2025 Ban, Gao, Zhou and Bao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. The differential role of IL-33 and IL-38 in prostate cancer, contradictory roles Runfen Ban 1†, Shanshan Gao 1†, Bin Zhou 2* and Shisan Bao 3* 1 Department of Urology, Gansu Provincial People’s Hospital, Lanzhou, China, 2 Haemodialysis Centre, Gansu Provincial People’s Hospital, Lanzhou, Gansu, China, 3Scientiﬁc Research Division, The First People’s Hospital of Baiyin, Gansu, China Prostate cancer (PCa) is still as a major cause of morbidity and mortality in men atthe global level, highlighting the necessity for improved diagnostic and therapeutic strategies beyond current PSA screening limitations. This minireview focuses on the complex and often opposing roles of two key cytokines, IL-33 and IL-38, within the tumour microenvironment and their implications for host immunosurveillance in PCa. Intra-tumoral IL-33 expression is signiﬁcantly reduced in PCa tissues and correlates with aggressive disease features such as higher Gleason scores and lymphatic metastasis, suggesting an inherent antitumour function. Such a protective role may be mediated via the ST2/NF-kB signalling pathway and the recruitment of lymphocytes into the tumour microenvironment. However, a paradoxical increase in circulating IL-33 levels in PCa patients hints at complex systemic compensatory mechanisms or differential compartmental regulation. In contrast, intra-tumoral IL-38 exhibits markedly elevated expression in PCa compared to benign prostatic hyperplasia and non-cancerous tissues. This increased IL-38 correlates with tumour severity, advanced TNM stages, and poorer overall survival, indicating a pro-tumoral role. Mechanistically, IL-38 appears to inhibit CD8+ cytotoxic T cell inﬁltration and potentially promotes immunosuppression through the upregulation of regulatory T cells (Tregs), thereby facilitating tumour progression . The contrasting expression patterns and clinicopathological associations of IL-33 and IL-38 highlight their potential as novel biomarkers for PCa diagnosis and prognosis. Further comprehensive investigation, including multi-centre studies across diverse populations, functional in vitro and in vivo analyses, and exploration of their therapeutic targetability, is crucial to translate these ﬁndings into effective precision medicine strategies for PCa patients. KEYWORDS IL-33, IL-38, prostate cancer, precision medicine, diagnosis Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) Introduction Despite extensive basic and clinical research and signiﬁcant advancements in medical interventions for prostate cancer (PCa) (1), PCa remains the second most common cancer and the ﬁfth leading cause of cancer-related deaths among men globally (2) . The global burden is considerable, with approximately 1.4 mil

FAQs

How do IL-33 levels differ between prostate cancer and non-cancer tissues?

IL-33 expression within tumors is significantly reduced in prostate cancer compared with reference tissues. Lower IL-33 also aligns with more aggressive disease characteristics.

What clinical associations are linked to IL-38 in prostate cancer?

IL-38 is markedly elevated in prostate cancer relative to benign prostatic hyperplasia and non-cancerous tissues. Higher IL-38 correlates with tumor severity, advanced TNM stage, and poorer overall survival.

Why do IL-33 and IL-38 have contradictory roles in prostate cancer?

The review reports opposing expression patterns and clinicopathological links: IL-33 is associated with antitumor protection, while IL-38 aligns with pro-tumoral immunosuppression. Mechanistically, IL-38 may inhibit CD8+ cytotoxic T-cell infiltration and promote Treg-related immunosuppression.

Sep 23, 2026

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