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.