Immune checkpoint inhibitors in bladder cancer: from mechanistic insights to emerging combination frontlines

Bladder cancer (BC), primarily urothelial carcinoma, remains one of the most common and lethal genitourinary malignancies worldwide, with limited long-term outcomes from standard treatments such as chemotherapy and radical cystectomy. These conventional modalities often fail to achieve durable responses and can severely affect patients’ quality of life, underscoring the need for more effective and targeted therapeutic strategies. Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte–associated protein 4 (CTsLA-4) have revolutionized BC therapy by restoring antitumor immune function. Nevertheless, treatment resistance, immune-related adverse events, and patient heterogeneity continue to limit their universal efficacy. This review provides an in-depth overview of ICI mechanisms and highlights evolving therapeutic approaches, including combination strategies with chemotherapy, radiotherapy, Bacillus Calmette–Guérin (BCG), and antibody–drug conjugates (ADCs). It also discusses emerging biomarkers such as PD-L1 expression, tumor mutational burden (TMB), and DNA damage repair (DDR) deficiency as predictive tools for treatment selection. Overall, this study underscores the pivotal role of immunotherapy in reshaping bladder cancer management and outlines future directions toward safe, personalized, and biomarker-driven therapeutic paradigms.