Sig27 stratifies prostate cancer recurrence by assessing the immunosuppressive properties of tumors

Prostate cancer (PC) remains a leading cause of cancer-related mortality in men, with recurrence contributing significantly to poor outcomes. Its molecular heterogeneity complicates effective risk stratification. We evaluated Sig27, a novel 27-gene panel, across 13 bulk RNA-seq datasets ( n = 3,133 tumors) and 6 single-cell RNA-seq (scRNA-seq) datasets ( n = 53 patients). Sig27 expression was elevated in PC compared to normal tissue and further increased in high-grade Gleason tumors, node-positive, and recurrent tumors. Sig27 demonstrated recurrence prediction comparable to Oncotype DX, with strong enrichment in immune regulatory pathways. To further investigate immune associations, we developed SigIC, a 22-gene immune checkpoint panel. Sig27 showed strong correlations with SigIC and individual immune checkpoints (e.g., HAVCR2, CD96, TIGIT) in both primary and metastatic PC. In scRNA-seq data, Sig27 was enriched in tumor-associated monocytes/macrophages (TAMs) and endothelial cells. We identified five key Sig27 genes – TFEC, FPR3, NOD2, LAMP3, and MCTP1 – and constructed Sig27IMG, a multigene panel formed by these five genes, and demonstrated their robust correlations with immune checkpoints and their strong enrichment in TAMs and endothelial cells. Sig27IMG strongly predicted PC recurrence and was dominantly expressed in TAMs, dendritic cells, and endothelial cells across 26 cancer types ( n = 386 patients) in scRNA-seq studies and 17 cancer types ( n = 5,672 patients) in bulk RNA-seq investigations. Notably, Sig27IMG stratified patients with a poor prognosis risk in these 17 cancer types. In summary, Sig27 and its derivative panel, Sig27IMG, offer a robust assessment of PC recurrence, highlighting immunosuppressive features mediated by TAMs, dendritic cells, and endothelial cells across multiple cancer types.