The emerging clinical landscape of circulating tumor DNA in bladder cancer and renal cell carcinoma from tumor-specific biology to detection strategies and translational hurdles

The diagnosis and monitoring of bladder cancer and renal cell carcinoma (RCC) depend mainly on cystoscopy, tissue biopsy, and imaging. These conventional methods have limitations for repeated sampling, real-time monitoring, and detecting small lesions. As a key component of liquid biopsy, circulating tumor DNA (ctDNA) can provide tumor-specific molecular information from plasma or urine with minimal invasiveness. Recently, ctDNA has shown broad utility in bladder cancer and RCC. It can aid diagnosis, support molecular classification, monitor postoperative minimal residual disease (MRD), evaluate recurrence risk, and assess treatment response. However, the feasibility of ctDNA differs between these two cancers. Bladder cancer lesions directly contact urine, allowing urine ctDNA to effectively capture local signals. This makes urine ctDNA particularly promising for lesion detection and recurrence monitoring. In contrast, RCC often releases limited ctDNA, increasing false-negative results, especially in localized disease. Currently, ctDNA applications in RCC focus more on dynamic monitoring and complementary molecular profiling in advanced stages. This narrative review explains the biology of ctDNA, covers main detection platforms, and discusses applications in bladder cancer and RCC, following the concept of “tumor release biology—sample accessibility—clinical problem adaptability.” It examines PCR-based technologies and next-generation sequencing (NGS) across different clinical settings, highlighting advances in postoperative MRD monitoring, immunotherapy response evaluation, and targeted therapy stratification. The review also addresses challenges hindering clinical translation, including complex urine sample preparation, limited sensitivity in low tumor burden, interference from clonal hematopoiesis of indeterminate potential (CHIP), cross-platform discrepancies, and insufficient cost-effectiveness data. Based on current evidence, ctDNA is poised for initial use in urine-based detection and perioperative risk assessment in bladder cancer. For RCC, translation requires better understanding of its low-release characteristics and integration of multi-omics strategies. Future work should standardize pre-analytical and analytical procedures, develop frameworks for interpreting negative ctDNA results, and test ctDNA-guided strategies in prospective decision-oriented studies.