Circulating biomarkers in bladder cancer: emerging evidence and future directions for personalized therapy

Bladder cancer diagnosis and surveillance remain anchored in cystoscopy and urine cytology, despite their invasiveness, operator dependence, and limited sensitivity for low-grade or flat lesions. These constraints have accelerated interest in liquid biopsy approaches that provide noninvasive, real-time molecular insights into tumor biology. This narrative review examines emerging evidence on three key classes of circulating biomarkers, namely, circulating tumor DNA (ctDNA), exosomes, and circulating tumor cells (CTCs), and their expanding roles in diagnosis, prognosis, and treatment guidance. ctDNA reflects tumor-specific genomic alterations and shows particular strength in detecting minimal residual disease, identifying early molecular relapse, and monitoring therapeutic response, although its diagnostic sensitivity remains moderate. Urinary exosomes demonstrate some of the highest diagnostic accuracies among liquid biopsy platforms, with multimarker RNA panels achieving sensitivities and specificities above 90%, while their diverse cargo of miRNAs, mRNAs, and lncRNAs provides robust prognostic information linked to recurrence and survival. CTCs, although technically challenging to isolate owing to their phenotypic heterogeneity, offer valuable insights into tumor aggressiveness, metastatic potential, and treatment responsiveness, especially in muscle-invasive disease. Advances in ultrasensitive sequencing, microfluidic CTC capture, and multi-omics integration are accelerating clinical translation. Collectively, circulating biomarkers are poised to complement and, in selected contexts, transform bladder cancer management by enabling earlier detection, individualized risk stratification, and more precise therapeutic decision-making.