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

Prostate cancer (PCa) is still as a major cause of morbidity and mortality in men at the global level, highlighting the necessity for improved diagnostic and therapeutic strategies beyond current PSA screening limitations. This mini-review 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 anti-tumour function. Such a protective role may be mediated the ST2/NF-κB 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 and analyses, and exploration of their therapeutic targetability, is crucial to translate these findings into effective precision medicine strategies for PCa patients.