Prostate Cancer: Dissecting Novel Immunosuppressive Mechanisms Through Context-Specific Transcriptomic Programs and...

Prostate cancer remains largely refractory to immunotherapy, implying the existence of context-specific immune landscape programs that diverge between circulation and tumor. Here, we integrate bulk RNA sequencing from three cohorts (patient peripheral mononuclear cells, primary prostate tissue, and biochemical-recurrence tumors) with multiparameter flow cytometry, unsupervised UMAP/T-REX (Tracking Responders Expanding) mapping, and de novo discovery of long non-coding RNAs (lncRNAs) to characterize context-specific immunoregulation. Patient PBMCs revealed a coherent IL-1/TNF/IL-17 inflammatory architecture with strong chemotactic programs and an unexpected neutrophil-like signal despite density-gradient isolation, consistent with low-density PMN-MDSCs. In contrast, tumors broadly repressed chemokines and innate immune mediators, yet upregulated prostate cancer-associated lncRNAs, indicating local immune quiescence coupled with non-coding regulatory programs. Recurrent tumors acquired epithelial-mesenchymal transition and metabolic remodeling, accompanied by relapse-associated lncRNA signatures, whereas long-term nonrecurrent tumors preserved epithelial and stress-response networks. High-dimensional cytometry confirmed discrete, cancer-enriched myeloid clusters expressing CD47, SIRPα, PD-L1, CD73, and Galectin-9. Network analysis highlighted inflammatory hubs (CXCL2, PTGS2) in PBMCs and loss of mechanotransduction modules in tumors. Structural modeling uncovered a three-way junction and 3' triple helix in lncRNA. Collectively, these data suggest that circulating inflammatory rewiring is associated with checkpoint-rich suppressor expansion and tumor immune quiescence, outlining integrated myeloid- and RNA-directed strategies for cancer research.