Antibody-Mediated Therapies in Urothelial Carcinoma: A Critical Narrative Review

Urothelial carcinoma (UCC) remains a clinical challenge due to its high recurrence rate and aggressive advanced-stage behavior. Driven by a high tumor mutational burden and the consistent overexpression of surface antigens, including Nectin-4, Trop-2, and HER2, UCC has become a prime target for antibody-mediated therapies. Although both immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) show significant clinical efficacy, their rational combination further enhances antitumor activity via immunogenic cell death. However, therapeutic resistance and immune evasion still limit response durability in many patients. This review provides a comprehensive overview of the molecular principles, mechanisms of action, and clinical efficacy of antibody-based UCC therapies. Additionally, we analyze biomarkers for patient selection, the mechanisms underlying resistance development, and the rationale for ADC-ICI combinations. By evaluating current challenges and unmet needs, this review aims to clarify the evolving therapeutic landscape and suggest future directions for optimizing UCC treatment.