Abstract
High-risk non–muscle invasive bladder cancer poses therapeutic challenges, with significant rates of recurrence and progression with standard intravesical bacillus Calmette-Guérin (BCG) therapy. Current surveillance strategies lack accurate risk stratification models to predict individual treatment response and personalized treatment options. Simultaneously, there are no well-validated alternatives to replace the current gold-standard approach based on clinical and pathologic features. This review examines emerging biomarkers and advanced technologies with the potential to enhance patient selection and personalize intravesical therapy in HR-NMIBC. Artificial intelligence(AI)-driven histopathologic tools, such as the computer histological AI biomarker, have demonstrated the ability to identify non-responders to standard therapy using whole-slide digital pathology images. In parallel, radiomics-enhanced imaging has shown promise in assessing tumor biology and immune microenvironment features predictive of BCG responsiveness. Liquid biopsy, especially urine tumor DNA analysis, is now available in the arsenal to detect minimal residual disease, stratify recurrence risk, and predict treatment response even before clinical or radiographic evidence of recurrence. Tissue-based genomic profiling has also revealed molecular alterations associated with treatment resistance, though additional validation is needed. Together, these next-generation biomarkers may represent a pivotal shift toward precision oncology in bladder cancer and their incorporation into NMIBC future clinical guidelines is both anticipated and necessary.