Core Viewpoint - The article discusses a novel urine liquid biopsy method developed to enhance the prediction of bladder cancer patients' responses to surgery and Bacillus Calmette-Guérin (BCG) treatment, addressing the limitations of current diagnostic methods due to the "field effect" [3][6][17]. Group 1: Background and Challenges - Non-muscle invasive bladder cancer (NMIBC) is a common type where patients typically undergo tumor resection followed by BCG immunotherapy, but BCG is not effective for all patients, and predictive biomarkers are lacking [6]. - Urine tumor DNA (utDNA) analysis is a non-invasive monitoring method, but the presence of somatic mutations in normal urothelial cells near tumors leads to false positives due to the "field effect," which acts as background noise [6][5]. Group 2: Innovative Methodology - The research team developed a statistical method named RePhyNERX to filter out mutations likely caused by the "field effect" by comparing tumor samples with normal tissues or post-treatment urine, significantly improving the specificity of utDNA detection [8][7]. - In a training cohort, the use of post-treatment urine for filtering yielded the best results, effectively distinguishing patient prognoses with a hazard ratio (HR) of 12.6, indicating a reduction in false positives [8]. Group 3: Clinical Validation - The study prospectively collected urine samples from 61 NMIBC patients undergoing BCG treatment, analyzing samples before surgery, before BCG treatment, and after treatment [10]. - Patients were categorized into three molecular response types: 1. Complete surgical responders: 39.3% had negative utDNA post-surgery, potentially curable by surgery alone 2. BCG responders: 27.9% had positive utDNA pre-treatment but significant decline post-treatment 3. Non-responders: 32.8% had persistent or rising utDNA post-treatment [10][11]. Group 4: Molecular Mechanisms - The research identified biomarkers distinguishing surgical responders from BCG responders, noting that BCG responders had a higher tumor mutation burden (TMB) and enriched immune-related gene expression, indicating a pre-existing immune activation environment is necessary for BCG efficacy [13][12]. - A high T cell/stroma enrichment score (TSE) correlated positively with BCG response, similar to predictive markers for immune checkpoint inhibitors [14]. Group 5: Future Prospects - This research not only improves the accuracy of urine liquid biopsy but also paves the way for personalized treatment strategies, allowing utDNA negative patients to potentially avoid unnecessary BCG treatment and reducing side effects, while positive patients can receive early intensified treatment [17]. - The method has potential applications in other cancers, such as lung and head and neck cancers, addressing the "field effect" issue [18].