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

Abstract

Prostate cancer remains a major health burden with limited success in immune-targeted therapies. To identify immune-cell-resolved genetically prioritized 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 eGene-cell-type associations supported by both genetic association and shared-signal evidence, with prominent representation in CD4+ and CD8+ T-cell subsets. Functional analyses revealed enrichment in immune-related pathways such as antigen processing and cytokine signaling. Meta-analysis identified 52 nominally significant eGene-cell-type associations involving 25 unique genes. Single-cell transcriptomics further mapped the expression of prioritized genes, including HLA-DQA2, TXN, and COX6B1, across immune populations within the prostate tumor microenvironment. Drug-target mapping highlighted candidate pharmacological connections involving genes such as IGF1R and FAAH, with known drug interactions mapped via DrugBank and STRING. Our integrative framework identifies immune-cell-resolved genetic associations with prostate cancer susceptibility and prioritizes candidate targets for further functional and pharmacological investigation. These findings provide a high-resolution resource for studying genetically informed tumor-immune mechanisms and therapeutic hypotheses in prostate cancer.