Precision medicine in bladder cancer: Redefining treatment paradigms through ADCs, immunotherapy, and molecular subtyping.

Bladder cancer, particularly in its muscle-invasive and advanced urothelial carcinoma forms, has long been constrained by the therapeutic ceiling of platinum-based chemotherapy, with a substantial proportion of patients deemed ineligible for cisplatin due to comorbidities, underscoring an urgent unmet need for novel treatment modalities. The introduction of immune checkpoint inhibitors targeting the PD-1/PD-L1 axis marked a paradigm shift in the therapeutic landscape, solidifying immunotherapy(IO) as a foundational strategy. More recently, antibody-drug conjugates(ADCs) have emerged as transformative therapeutic agents, demonstrating substantial clinical efficacy through their targeted delivery of cytotoxic payloads. The validation of Enfortumab Vedotin (EV) combined with Pembrolizumab as a first-line regimen has established a new standard of care, representing a transition toward combination strategies that integrate cytotoxic precision with immune activation. Simultaneously, molecular profiling has facilitated the development of targeted therapies, such as FGFR inhibitors, for genetically defined subpopulations, advancing the field toward precision oncology. This review comprehensively examines the evolution of systemic therapy in bladder cancer, critically analyzing the mechanistic rationale for combining IO with ADCs, elucidating resistance mechanisms, and exploring molecular subtype-guided treatment algorithms. Furthermore, it discusses emerging therapeutic classes, including bispecific ADCs and cancer vaccines, and outlines future directions for dynamic biomarker-driven strategies to optimize patient selection and therapeutic sequencing.