Integrative Analysis Uncovers SETD5 as an Epigenetic Regulator of Transcriptional and Immune Tumor Programs Across Human Cancers

SETD5 (SET domain-containing 5) is a chromatin-associated regulator increasingly recognized as dysregulated in human malignancies; however, its contribution to tumor biology and tumor–immune interactions remain undefined. We performed an integrative pan-cancer multi-omics analysis to define the landscape of SETD5 dysregulation across cancer types. Transcriptomic, genomic, and epigenetic datasets were integrated to evaluate SETD5 alterations and molecular associations. Protein interaction and pathway enrichment analyses were conducted using STRING, GO, and KEGG, and immunogenomic profiling was used to interrogate associations between SETD5 expression, immune infiltration, and checkpoint programs. SETD5 was overexpressed across multiple malignancies, with low mutation frequency but recurrent copy-number gains. Promoter hypomethylation was detected in a subset of tumors with increased SETD5 expression, suggesting a possible association with epigenetic regulation. Pathway analyses linked SETD5 to macromolecule methylation and transcriptional regulation. SETD5 expression correlated positively with infiltration of macrophages, neutrophils, and dendritic cells, whereas associations with CD8+ and CD4+ T cells varied by tumor type. Tumor type-specific correlations were observed between SETD5 and immune checkpoints genes, including PD-L1 and TIM-3, suggesting an association with immunoregulatory tumor states. These findings identify SETD5 as a recurrently deregulated epigenetic regulator and highlight its potential role in transcriptional control and tumor immune modulation.