Gene-mediated therapy for BCG-unresponsive nonmuscle-invasive bladder cancer: mechanisms, clinical evidence, and practical implementation

PURPOSE OF REVIEW: Gene therapy has emerged as an attractive bladder-sparing strategy for patients with high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle-invasive bladder cancer (NMIBC), addressing a therapeutic gap for those ineligible for or declining radical cystectomy. This review aims to describe the recent advances in gene-mediated therapies for BCG-unresponsive NMIBC. RECENT FINDINGS: The bladder's unique anatomy with direct intravesical access and capacity for high local exposure with minimal systemic absorption provides an ideal context for gene delivery. Advances in barrier modulation with Syn3 and vector engineering have enabled efficient delivery. Adenoviral vectors as illustrated by the FDA-approved nadofaragene firadenovec (Adstiladrin), and other platforms, such as the conditionally replicating oncolytic adenoviruses (cretostimogene, CG0070), are maturing. Combination regimens of gene therapy and immune checkpoint inhibitors have shown additive or synergistic activity, deepening durability of gene therapy. Novel advancements including urinary and plasma tumor DNA are emerging as predictive biomarkers to guide patient selection, monitor minimal residual disease, and trigger early salvage. SUMMARY: Gene-mediated therapy is gradually advancing NMIBC care, with expanding indications and potent combinations positing itself to improve bladder preservation and long-term outcomes.