Research progress and clinical translation prospects of multiple urinary biomarkers in non-invasive diagnosis of urothelial carcinoma

Abstract

Urothelial carcinoma is a common urinary malignancy with high incidence, recurrence, and mortality. Early diagnosis is pivotal for improving patient outcomes. Current standards have important limitations: cystoscopy, although the cornerstone of diagnosis and surveillance, is invasive and costly, while cytology has limited sensitivity for low-grade or early-stage lesions. Urine, as a liquid biopsy, offers a non-invasive and repeatable approach for sampling urogenital pathology, with the potential for longitudinal monitoring through serial collection. The review covers urinary multi-omics biomarkers, including cfDNA/methylation, miRNAs, extracellular vesicles (EVs), and proteomic/metabolomic signatures. We summarize their performance in early detection, staging, and postoperative monitoring. Integrated multi-analyte models, including true multi-omics assays and multiplex single-omics panels, generally outperform single biomarkers, with some panels achieving >90% sensitivity and >95% specificity in prospective cohorts. Despite progress, several challenges remain: standardization, large-scale prospective validation, and regulatory/reimbursement barriers. We conclude that urinary multi-omics diagnostics are promising complementary tools that may optimize surveillance and risk stratification. Still, limited prospective validation, lack of standardization, and the persistent risk of false-negative results constrain adoption. On current evidence, they are not positioned to replace cystoscopy, which remains the cornerstone of diagnosis and surveillance, particularly in non-muscle-invasive bladder cancer (NMIBC). However, their most realistic and immediate clinical role is as a triage tool to optimize the selective use of cystoscopy—particularly for risk-stratifying patients with hematuria, adjudicating equivocal cytology, and potentially reducing the frequency of invasive surveillance in low-risk NMIBC patients.