STAT1 and m⁶A-mediated IL15RA upregulation promotes metastasis via ZEB1/NF-κΒ axis in ccRCC

Interleukin-15 receptor alpha (IL15RA) demonstrates critical regulatory function in oncogenesis and immunomodulation across various malignancies. However, the role of IL15RA in cancers, such as Clear Cell Renal Cell Carcinoma (ccRCC) remains unclear. Therefore, integrated pan-cancer analysis and mechanism investigation assays are essential for IL15RA-directed therapeutic strategy optimization in ccRCC. The comprehensive pan-cancer analysis reveals IL15RA as a plausible diagnostic and prognostic biomarker, as well as a promising immunotherapeutic target across various cancers, particularly ccRCC. IL15RA promotes ccRCC metastasis based on the data of the investigation. Mechanistically, STAT1 binds to IL15RA promoter region, thereby enhancing IL15RA mRNA expression, while METTL3 modulates RNA m⁶A methylation patterns to stabilize IL15RA transcription. Furthermore, IL15RA potentiates metastasis via NF-κΒ/ZEB1 axis in ccRCC. Drug sensitivity profiling further indicates that IL15RA expression increases sensitivity to chemotherapeutic agents in ccRCC patients. The findings demonstrate that IL15RA emerges as a critical prognostic indicator and immunotherapeutic biomarker particularly in ccRCC. Our findings underscore the necessity for comprehensive mechanistic studies to elucidate IL15RA's roles and are beneficial for advancing targeted therapeutic strategies in oncological interventions.