Beyond the BCG Paradox: Biological Rationale and Clinical Evidence for Combining Intravesical BCG with Immune Checkpoint Inhibitors in High-Risk Non-muscle-Invasive Bladder Cancer.

Bladder cancer (BC) is the most common malignancy of the urinary tract, with more than 75% of cases diagnosed as non-muscle-invasive bladder cancer (NMIBC). Intravesical Bacillus Calmette-Guérin (BCG) remains the gold standard adjuvant treatment for high-risk NMIBC owing to its ability to induce a robust local immune response within the bladder tumor microenvironment. Nevertheless, a substantial proportion of patients experience disease recurrence or progression, highlighting the need for improved therapeutic strategies. This narrative review examines the biological rationale and available clinical evidence supporting the combination of intravesical BCG with immune checkpoint inhibitors (ICIs) in high-risk NMIBC. A literature review was conducted to analyze the immunological mechanisms underlying BCG-induced antitumor activity, adaptive immune resistance, and the potential role of ICIs in modulating the tumor microenvironment. Clinical trials were evaluated with particular attention to patient populations, study design, safety profiles, and efficacy end points. From a biological perspective, BCG acts as an immunological primer by recruiting and activating innate and adaptive immune cells, while immune checkpoint inhibitors may counteract functional exhaustion of BCG-induced antitumor responses. However, translation of this rationale into consistent clinical benefit remains challenging. Early-phase studies have reported variable response rates in selected patient populations, particularly in BCG-unresponsive disease. In contrast, recent phase III data have shown that upfront combination strategies do not necessarily translate into improved oncological outcomes. Overall, while the combination of BCG and immune checkpoint inhibition is supported by a strong immunological rationale, current clinical evidence remains heterogeneous and largely derived from early-phase or ongoing trials, precluding definitive conclusions regarding long-term oncological benefit and durable bladder preservation. Despite a strong immunological rationale, the combination of BCG with immune checkpoint inhibitors remains investigational. Its adoption into routine clinical practice will require mature phase III evidence, validated predictive biomarkers, and a clear demonstration of superiority over established bladder-preserving treatment strategies.