Overcoming barriers to bladder preservation: Emerging intravesical therapies for high-risk non-muscle-invasive bladder cancer.

High-risk non-muscle-invasive bladder cancer (HR-NMIBC) remains prone to recurrence and progression after transurethral resection of bladder tumor. Intravesical bacillus Calmette-Guérin (BCG) has long served as the backbone of treatment for HR-NMIBC. However, no uniform bladder-preserving pathway has been established for patients with BCG-unresponsive disease. Although radical cystectomy (RC) offers the most dependable oncological control, perioperative morbidity, the impact on quality of life, and patient reluctance restrict its routine use in real-world practice. Previous studies revealed that an initial bladder-preserving approach may not compromise survival while avoiding the morbidity of upfront RC. Accordingly, there remains a need for intravesical approaches that provide durable disease control with an acceptable safety profile while preserving the bladder. This review summarizes current advances in intravesical therapy for HR-NMIBC, covering treatment strategies, emerging therapeutics, intravesical delivery technologies, and representative preclinical platforms. We also examine the major barriers that blunt the activity of emerging intravesical treatments, including short intravesical drug dwell time, urinary dilution, the urothelial permeability barrier, tumor heterogeneity, field cancerization, and an immunosuppressive tumor microenvironment. Collectively, these strategies aim to refine treatment for HR-NMIBC and may provide a framework for improving the durability of bladder-preserving therapy.