Mapping the immune landscape of PCa: From tumor microenvironment to therapeutics

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, yet its response to immunotherapy is notably limited compared to other solid tumors. This resistance stems primarily from a highly immunosuppressive tumor microenvironment (TME), characterized by "cold" tumor features such as low mutational burden, scarce cytotoxic T cell infiltration and extensive regulatory cell populations. Building upon the "tumor ecosystem" concept, we integrate emerging insights from single-cell and spatial transcriptomics to decode the spatiotemporal heterogeneity of the PCa ecosystem. We specifically highlight the underappreciated "neural-immune-microbiome" axis-a triangular regulatory network wherein sympathetic nerves suppress T cell motility, intratumoral microbiota drive chronic inflammation, and metabolic reprogramming creates lipid-mediated immune paralysis. We further dissect how cell-type specific remodeling mechanisms, particularly TREM2+ macrophage-mediated metabolic symbiosis, drive the transition from hormone-sensitive to castration-resistant disease. Furthermore, we critically assess how standard of care (ADT, chemotherapy, radiotherapy) and emerging agents (PARPi, HDACi) reprogram the immune landscape with time-dependent, often paradoxical effects. Finally, we propose a roadmap for precision oncology, emphasizing that future success lies in "ecological editing"-biomarker-driven patient stratification and rational combination strategies to overcome the physical and biological barriers of the TME.