Abstract
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a common, aggressive tumor with treatment challenges due to varied patient responses and ineffective biomarkers. mRNA-based therapeutic approaches, particularly in cancer immunology, have become an important area of research. This study investigates nucleoside diphosphate linked moiety X hydrolase 16 (NUDT16), a key enzyme involved in mRNA quality control through 5’ cap-dependent decapping, focusing on its expression profile and prognostic implications in clear cell renal cell carcinoma (ccRCC). METHODS: Utilizing a comprehensive multi-omics strategy, we integrated mRNA expression profiles from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) datasets (GSE68417 and GSE66270). We systematically evaluated NUDT16 expression across pan-cancer, ccRCC, and normal tissues, and assessed its association with clinical parameters. A prognostic model was developed using Cox proportional hazards regression and subsequently validated. Co-expressed genes of NUDT16 were subjected to functional enrichment analysis, and a protein-protein interaction network was constructed. We further investigated NUDT16’s role in immune infiltration, immunotherapy response, methylation status, and CpG site prediction in ccRCC. Single-cell omics analysis and functional assays were performed to elucidate NUDT16’s biological functions. RESULTS: NUDT16 expression was significantly downregulated in ccRCC compared to normal tissues, with progressive reduction observed across advancing pathological stages and histological grades. The prognostic model incorporating NUDT16 expression and clinicopathological features demonstrated robust predictive accuracy for ccRCC patient survival. Gene Set Enrichment Analysis (GSEA) of NUDT16 co-expressed genes revealed significant enrichment in biological processes related to proximal tubule transport and DNA methylation. NUDT16 expression exhibited significant correlations with immune infiltration patterns, particularly NK CD56bright, TReg, and Tcm cells. Reduced NUDT16 expression was associated with enhanced response to CTLA4(+)PD1(-) immune phenotype scores, increased tumor immune dysfunction and exclusion scores, and elevated tumor mutation burden. Promoter region hypermethylation of NUDT16 was significantly elevated in ccRCC and correlated with adverse survival outcomes. NUDT16 overexpression inhibited proliferation, colony formation, migration, and invasion in ccRCC cell lines (ACHN and 786-O). CONCLUSION: NUDT16 emerges as a potential prognostic biomarker in ccRCC, with its downregulation significantly associated with unfavorable clinical outcomes, altered immune infiltration profiles, and promoter region hypermethylation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-025-15035-6.