Urine-based PSMA detection for noninvasive prostate cancer diagnosis: recent advances, translational challenges, and future perspectives

Prostate cancer (PCa) is one of the most prevalent malignancies in men worldwide and continues to impose a substantial public health burden. Although prostate-specific antigen (PSA) testing remains the most widely used tool for PCa screening, its suboptimal specificity and moderate sensitivity, especially within the diagnostic gray zone of 4–10 ng/mL—frequently leads to unnecessary prostate biopsies, overdiagnosis, and overtreatment. Therefore, the development of sensitive, specific, and noninvasive diagnostic strategies has become a major priority in PCa management. Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein, is markedly overexpressed in PCa tissues and is closely associated with tumor aggressiveness, pathological progression, metastatic potential, and castration resistance. Owing to its strong disease association and established clinical relevance in molecular imaging and targeted therapy, PSMA has emerged as an attractive candidate for noninvasive diagnostic development. At the same time, urine has become an appealing liquid-biopsy substrate because it can be collected noninvasively, repeatedly, and with direct anatomical relevance to the prostate. Increasing evidence suggests that urinary PSMA-related analytes, including soluble PSMA, PSMA-positive extracellular vesicles (EVs), and associated transcripts, may provide a biological basis for noninvasive PCa detection. In this review, we summarize the biological rationale for PSMA as a urinary biomarker and critically examine recent advances in urinary PSMA detection technologies. Particular attention is given to antibody-based immunoassays and integrated biosensing systems that combine aptamer-mediated molecular recognition, CRISPR/Cas12a-assisted signal amplification, magnetic enrichment, and lateral flow assay (LFA) readout. We further discuss the major challenges hindering clinical implementation, including pre-analytical variability, urinary analyte heterogeneity, insufficient large-scale validation, and the limitations of single-biomarker strategies. Finally, future perspectives are outlined with emphasis on assay standardization, multimarker integration, and the development of clinically deployable point-of-care testing platforms. Collectively, urinary PSMA detection represents a promising but still emerging route toward more specific and noninvasive PCa diagnostics.