Integrating transcriptomics and Mendelian randomisation identifies immune-related genes causally linked to prostate cancer lymph node metastasis.

[UNLABELLED] Lymph node metastasis marks a critical transition in prostate cancer progression, yet causal molecular links between primary tumour immunity and metastatic capability remain unclear. We analysed 425 primary prostate cancer patients, integrating transcriptomic profiling with Mendelian randomisation to establish causal relationships between immune cell gene expression and lymph node metastasis. Differential expression analysis identified 131 significantly altered genes between N1 and N0 tumours. Functional enrichment revealed upregulated genes enriched in metal ion homeostasis, whilst downregulated genes involved viral defence and interferon signalling. Mendelian randomisation identified 11 significant causal associations, with 73% demonstrating protective effects. MT1F showed consistent protection across immune cell types, whilst CD38, GNMT, and SLC14A1 paradoxically increased risk despite upregulation in metastatic tumours. A 7-gene prognostic signature independently predicted progression-free survival across validation cohorts. Immune deconvolution analysis revealed high-risk tumours exhibited an immunosuppressive microenvironment with increased regulatory T cells and M2 macrophages, whilst individual signature genes paradoxically showed positive correlations with anti-tumour plasma cells. This study reveals the paradoxical nature of immune-related genes: promoting metastasis when expressed in cancer cells whilst providing protection when expressed in immune cells. Systematic immune suppression creates corrupted microenvironments where protective genes are co-opted for cancer survival. Effective immunotherapy strategies must account for this dual nature, necessitating multi-dimensional precision medicine approaches that target specific cellular compartments.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s12672-026-04488-1.