Single-cell transcriptome-wide Mendelian randomization and colocalization analyses reveal immune-cell-specific mechanisms and actionable drug targets in prostate cancer

Prostate cancer remains a major health burden with limited success in immune-targeted therapies. To identify immune-cell-specific therapeutic targets, we integrated single-cell cis-eQTL data across 14 immune cell types, bulk eQTLs, GWAS summary statistics from PRACTICAL and FinnGen, and single-cell RNA-seq data from prostate tumors. Using Mendelian randomization and Bayesian colocalization, we prioritized 80 causal eGenes with shared genetic signals, especially in CD4 and CD8 T cells. Functional analyses revealed enrichment in immune-related pathways such as antigen processing and cytokine signaling. Meta-analysis validated 52 robust eGenes across cohorts. Single-cell transcriptomics confirmed cell-type-specific expression of key genes including HLA-DQA2, TXN, and COX6B1 within the tumor microenvironment. Drug repurposing analysis identified potential therapeutic targets such as IGF1R and FAAH, with known drug interactions mapped via DrugBank and STRING. Our integrative framework highlights immune-cell-specific genetic drivers and actionable targets in prostate cancer, offering a high-resolution resource for precision immunotherapy development.