Modeling Urothelial Carcinoma and Immunotherapy Response Using Organoid Platforms: From Epithelial Tumor Organoids to Multilineage Systems.

Cancer immunotherapy has transformed oncology, including the management of urothelial carcinoma, yet response rates remain limited and mechanisms of resistance are incompletely understood. At the same time, recent initiatives from the National Institutes of Health and the United States Food and Drug Administration have emphasized the development of standardized human organoid platforms to improve preclinical modeling and reduce reliance on traditional animal systems. Urothelial cancer provides a compelling context in which to advance these efforts, given its established responsiveness to Bacillus Calmette-Guérin and immune checkpoint blockade and its marked heterogeneity in clinical outcomes. Here, we review current organoid-based platforms for modeling bladder cancer immunotherapy, including patient biopsy-derived epithelial tumor organoids, air-liquid interface cultures that retain endogenous stromal and immune components, engineered bladder cancer assembloids that reconstruct defined multicellular circuits, and induced pluripotent stem cell-derived urothelial organoids that offer renewable multilineage systems. For each approach, we outline strengths, technical constraints, and limitations in scalability, immune fidelity, and genetic matching. We conclude by discussing the critical challenges that must be addressed-including benchmarking to patient tumors, reproducibility across laboratories, and standardized validation metrics-to enable regulatory acceptance and clinical translation of organoid-based immunotherapy testing.