Immune checkpoint inhibitors in BCG-unresponsive non-muscle-invasive bladder cancer: a narrative review of evidence and future directions.

Abstract

<h4>Background and objective</h4>Non-muscle-invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG) therapy poses a significant clinical challenge, as the standard intervention of radical cystectomy (RC) is associated with substantial morbidity. Immune checkpoint inhibitors (ICIs) have emerged as a promising strategy that may enable bladder preservation. This review critically evaluates current evidence regarding the efficacy and safety of ICIs in this high-risk patient population, aiming to inform clinical decision-making and guide future research.<h4>Methods</h4>A comprehensive literature search was conducted in PubMed and Web of Science up to July 2025. The search strategy combined keywords and Medical Subject Headings (MeSH) terms related to bladder cancer, ICIs, and BCG treatment failure. Only studies published in English were included.<h4>Key content and findings</h4>This review integrates findings from key clinical trials evaluating ICIs, such as pembrolizumab and atezolizumab, used alone or alongside BCG, emphasizing their capacity to elicit sustained therapeutic benefits. It also examines the significance of predictive biomarkers, including programmed death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and characteristics of the tumor microenvironment. In addition, the review outlines current approaches for detecting and managing immune-related adverse events (irAEs).<h4>Conclusions</h4>ICIs represent a promising therapeutic avenue for patients with BCG-unresponsive NMIBC, supporting a shift toward bladder-preserving management strategies. Future research should focus on biomarker-guided patient selection and explore combination regimens to optimize clinical outcomes, thereby informing both clinical practice and investigational priorities.