Blood and urine-based biomarkers in prostate cancer: Current advances, clinical applications, and future directions.

Prostate cancer (PCa) is one of the most prevalent malignancies in men, characterized by high clinical and molecular heterogeneity. Despite the widespread use of prostate-specific antigen (PSA) for diagnosis and monitoring, its limited specificity and sensitivity necessitate the development of more accurate biomarkers. This review provides a comprehensive overview of current and emerging diagnostic, prognostic, and predictive biomarkers in PCa, highlighting their clinical applications and future perspectives. PSA, though historically central in PCa screening, lacks tumor specificity, often leading to unnecessary biopsies or missed aggressive cancers. Recent blood-based biomarkers, such as the Prostate Health Index (PHI) and 4Kscore, improve specificity by integrating PSA isoforms or kallikrein protein levels with clinical parameters. Urine-based biomarkers like PCA3 and SelectMDx further enhance diagnostic precision, particularly in distinguishing high-grade tumors, and show potential in active surveillance settings. Prognostic markers such as Bcl-2, Ki-67, and EZH2, alongside genetic alterations like MCM7 and 8q gain, help stratify patients by tumor aggressiveness and risk of recurrence. Liquid biopsies, including circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), offer non-invasive alternatives for molecular profiling, especially in metastatic castration-resistant PCa (mCRPC), and can identify actionable alterations such as BRCA1/2 or ATM mutations. Emerging technologies such as machine learning and single-cell omics are reshaping biomarker discovery. Artificial intelligence-driven models, like the replication stress signature (RSS), show promise in predicting relapse and therapeutic response. Single-cell RNA sequencing and spatial transcriptomics have deepened our understanding of PCa heterogeneity, tumour microenvironment, and resistance mechanisms. Furthermore, novel biomarkers, including exosome RNAs and immune-related markers (PD-L1, SOX2, TcellinfGEP), offer insights into tumour progression and immunotherapeutic potential. The urinary and gut microbiomes are also being explored for their diagnostic and prognostic roles in PCa. In conclusion, integrating advanced molecular tools and biomarker-guided platforms into clinical practice can significantly enhance early detection, personalized treatment, and monitoring in prostate cancer, paving the way for precision oncology.