Bladder cancer (BC) is a significant global health burden, ranking as the ninth most common cancer worldwide, with nearly half a million new cases reported annually (1). BC encompasses two primary categories: Muscle-invasive BC (MIBC) and non-MIBC (NMIBC). Notably, NMIBC constitutes ~75% of BC cases and encompasses various pathological stages, including non-invasive bladder carcinoma confined to the epithelium or mucosa, tumor invading the subepithelial connective tissue and carcinoma in situ (2). Despite its generally favorable prognosis, NMIBC presents distinct challenges, particularly in high-risk subsets, such as those with high-grade tumors, large tumor size, multifocality and those with a history of prior recurrence (3). These subsets demonstrate significant rates of recurrence and progression. For example, patients with carcinoma in situ or those with a high number of early recurrences within the first year after initial treatment are considered at higher risk for progression to MIBC (4). BC has a multifactorial etiology, with smoking being the primary risk factor for its development. While the majority of BC tumors originate from urothelial cells, histological variations, such as squamous, neuroendocrine, micropapillary and sarcomatoid subtypes are less common. Notably, the classification of BC into NMIBC and MIBC guides therapeutic approaches (5,6). Moreover, the prognosis and treatment decisions for NMIBC are heavily influenced by tumor grading, depth of invasion and risk stratification systems, such as those developed by the European Organization for Research and Treatment of Cancer and the European Association of Urology (7,8).

The cornerstone of initial treatment for intermediate- and high-risk NMIBC involves transurethral resection of the bladder tumor followed by adjuvant therapy with intravesical Bacillus Calmette-Guérin (BCG) (9). This approach is considered the standard of care for these tumors. BCG therapy, pioneered by Morales (10), has demonstrated efficacy in reducing the risk of disease progression and recurrence. However, its use is limited by the associated adverse events and recent shortages. Despite its benefits, a subset of patients with high-risk factors, such as those with carcinoma in situ, multiple recurrent tumors or BCG failure, fail to achieve an adequate therapeutic response, necessitating alternative treatment approaches (11,12).

BC, particularly NMIBC, is predominantly treated with intravesical BCG therapy (13). However, resistance to BCG therapy remains a significant clinical challenge. This resistance is often associated with the expression of immunosuppressive molecules, such as programmed death ligands [programmed death ligand 1 (PD-L1) and programmed cell death 1 ligand 2], which can inhibit the immune response and hinder the effectiveness of treatment (14). Experimental studies have demonstrated that the upregulation of these ligands in the tumor microenvironment is linked to poor BCG response, as they interfere with T cell activation and tumor immunosurveillance (15,16).

Furthermore, the global shortage of BCG has created notable challenges in managing NMIBC. Production issues, increased demand and regulatory challenges have contributed to the scarcity of BCG, thereby impacting treatment protocols worldwide (17). These shortcomings necessitate alternative treatment strategies, including the use of intravesical chemotherapy or other immunotherapeutic agents, such as pembrolizumab (18). Mitomycin C, gemcitabine and docetaxel have been explored as substitutes. However, their efficacy and long-term outcomes compared with BCG are still under evaluation (19). Consequently, healthcare systems have had to adapt by prioritizing BCG allocation for high-risk patients and utilizing alternative treatment regimens for those with lower-risk profiles. Ongoing research and development efforts aim to address these shortcomings by improving the production processes and developing new immunotherapeutic options (13,20).

Food and Drug Administration-approved injectable immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma represent a new era of treatment (21). These ICIs show promise as second-line treatments for BCG-unresponsive NMIBC, either alone or in combination with other agents (22). However, systemic administration leads to more adverse events, prompting the exploration of alternative delivery routes. Notably, intravesical ICIs offer a strategy for enhancing the therapeutic index and reducing systemic toxicity (23). Preliminary studies, such as the combination of intravesical pembrolizumab with BCG induction therapy for patients with BCG-unresponsive NMIBC, showed encouraging outcomes, improving recurrence-free survival and progression-free survival (PFS) (24–26). Other ICIs, such as atezolizumab, avelumab and nivolumab, have also demonstrated potential in this setting, revolutionizing the treatment landscape for NMIBC, particularly in cases of BCG failure. Ongoing research continues to explore novel agents and combination approaches to further optimize outcomes and reduce adverse events (27,28).

The present study aimed to evaluate the efficacy and safety of immunotherapy in BCG-refractory NMIBC by comparing intravesical BCG with novel ICIs. Through a meta-analysis of clinical trials and randomized controlled trials (RCTs), the impact of ICIs on overall survival (OS) and progression-free survival (PFS), along with their safety profiles were assessed. Additionally, response predictors were identified and future directions for optimizing treatment and biomarker development were explored. The findings provide insights to guide clinicians in selecting the most effective therapy based on individual patient characteristics.

Following the recommendations of the Preferred Reporting Standards for Systematic Reviews and Meta-Analyses 2020 guidelines (29) and the protocol registered in PROSPERO (https://www.crd.york.ac.uk/prospero/; no. CRD42024544722. The meta-analysis primarily compared BCG with ICIs (pembrolizumab/atezolizumab) in BCG-refractory NMIBC. Ethical approval was considered unnecessary as the study did not involve human or animal experiments.

The present systematic review and meta-analysis aimed to evaluate the efficacy and safety of ICIs compared with BCG therapy for BCG-refractory NMIBC, alongside exploratory comparisons with chemotherapy. The findings revealed that pembrolizumab and atezolizumab, two commonly used ICIs, demonstrated superior efficacy over chemotherapy and BCG across multiple clinical parameters, including tumor control, PFS and OS. Specifically, pembrolizumab showed significant benefits in managing tumor site, lymph node involvement, ECOG performance status and hematological outcomes, consistently outperforming BCG in tumor control, survival, and lymph node involvement. An increase in hemoglobin levels can be indicative of improved overall health and better systemic response to treatment (35), suggesting that pembrolizumab may contribute to enhanced treatment outcomes beyond tumor control, possibly through its immune-modulating effects. Despite higher incidences of certain adverse events, such as asthenia and pyrexia, ICIs were associated with a more favorable safety profile in managing anemia, fatigue and diarrhea. The overall heterogeneity in the analysis was moderate (I²=55%), with minimal variation across most subgroups, indicating consistent findings. These results suggest that ICIs, particularly pembrolizumab and atezolizumab, offer superior efficacy and a potentially more favorable safety profile compared with chemotherapy and BCG, marking them as promising treatment options for advanced NMIBC.

Pembrolizumab and atezolizumab have been extensively studied in patients with advanced urothelial carcinoma, with notable improvements in OS and durable responses observed in previous trials (36,37). For instance, a randomized phase 3 trial comparing pembrolizumab with standard chemotherapy regimens demonstrated a superior OS outcome with pembrolizumab, alongside favorable safety profiles (38). These findings align closely with the outcomes of the present meta-analysis, which also revealed significant improvements in OS with pembrolizumab and atezolizumab compared with chemotherapy in patients with advanced urothelial carcinoma.

Chemotherapy remains a cornerstone of BC treatment, albeit with varying efficacy and tolerability profiles among different agents (39,40). The present meta-analysis identified modest clinical benefits associated with various chemotherapy regimens, such as vinflunine, gemcitabine and taxanes, while highlighting significant toxicity concerns (41). Notably, while the present meta-analysis did not specifically analyze chemotherapy type and patient selection, the findings align with existing research emphasizing the role of these factors in optimizing treatment outcomes, as observed in a comparative study evaluating different chemotherapy regimens (42).

BCG therapy has long been established as the mainstay in the management of NMIBC, although its efficacy may be limited in patients who are unresponsive or intolerant to treatment (43). Emerging evidence suggests that combination therapies, such as pembrolizumab + BCG or atezolizumab + BCG, hold promise in improving treatment outcomes in these patients (44). The present meta-analysis contributes to this growing body of evidence by demonstrating the safety and potential efficacy of immunotherapy in advanced BC, particularly in the BCG-unresponsive NMIBC setting. While effective, intravesical BCG therapy is associated with several adverse events. Common side effects include cystitis, hematuria and flu-like symptoms, with severe complications such as sepsis being rare but notably concerning (45). In comparison, intravesical chemotherapy agents such as gemcitabine and docetaxel generally exhibit severe adverse events. For instance, gemcitabine has been associated with local side effects, such as irritative voiding symptoms and chemical cystitis, but systemic side effects are minimal (46,47). Moreover, the toxicity profile of docetaxel is also manageable, with less severe local toxicity compared with BCG (47). Pembrolizumab, an ICI, represents a novel approach for treating NMIBC, particularly in BCG-unresponsive cases (48). However, its side effects include immune-related adverse events, such as colitis, hepatitis and pneumonitis, which can be serious but are typically manageable with appropriate interventions (49). Although, pembrolizumab has a different side effect profile, its use in combination with BCG has been investigated to enhance therapeutic outcomes while effectively managing adverse effects (49,50). Furthermore, the findings of the present study resonate with those of comparative studies exploring similar combination therapies and treatment modalities. For instance, studies comparing pembrolizumab + BCG or atezolizumab + BCG with standard BCG therapy alone have consistently shown improved outcomes in terms of response rates and adverse event profiles (51,52). Hence, the comparative analyses in the present study provide additional support for the efficacy and safety of combination immunotherapy in BC management, reinforcing the relevance of the findings of the meta-analysis in the context of existing literature (53).

The strength of the present meta-analysis lies in the comprehensive inclusion of relevant studies evaluating the efficacy and safety of ICIs, BCG therapy and chemotherapy in BC treatment. By synthesizing data from multiple trials, a robust overview of the current evidence landscape has been provided, offering valuable insights into the comparative effectiveness of these therapeutic modalities. The combination of ICIs with BCG therapy was not explored in the present study as the analysis specifically aimed to compare the effectiveness of ICIs against standard therapies in patients with BCG-refractory NMIBC. The present study provides critical evidence to guide treatment decisions, particularly for BCG-unresponsive patients. Consequently, the findings suggest that ICIs, such as pembrolizumab and atezolizumab, offer improved efficacy and safety profiles compared with BCG, marking a promising therapeutic option for high-risk cases. These insights could influence clinical guidelines, promote personalized treatment strategies and improve patient outcomes. Nevertheless, further clinical trials are needed to optimize these combinations and establish the best treatment protocols. However, the findings of the present study suggest a promising shift toward more personalized and potent therapies in managing BCG-refractory NMIBC.

The limitations of the present study include potential publication bias, heterogeneity among the included studies, variations in study design and methodology and the inability to access individual patient data for more detailed analyses. Therefore, these factors may have influenced the overall interpretation of the results and should be considered when interpreting the findings of the present meta-analysis.