Recent advances in immunotherapy for bladder cancer: mechanisms, clinical applications, and future perspectives

The past decade has witnessed a paradigm shift in the treatment of bladder cancer, propelled by significant advances in immunotherapy. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4, adoptive cellular therapies including chimeric antigen receptor T-cell (CAR-T) therapy, oncolytic viruses, and novel immunomodulatory agents have transformed the therapeutic landscape for both non-muscle-invasive bladder cancer (NMIBC) and advanced urothelial carcinoma (UC). This review provides a comprehensive analysis of recent advances in bladder cancer immunotherapy, with a focus on underlying molecular and cellular mechanisms, key clinical trial evidence, and emerging resistance pathways. We highlight the rapidly expanding therapeutic roles of ICIs, alongside innovative modalities such as CAR-T cell therapy directed against tumor-associated antigens-including NECTIN4, PSMA, and FRα. Emerging immunotherapeutic targets and therapeutic modalities are comprehensively reviewed. We critically evaluate key clinical trials and systematically assess combination strategies-including ICIs combined with chemotherapy, radiotherapy, targeted therapy, or antibody-drug conjugates (ADCs). Key determinants of the tumor microenvironment (TME)-such as immunosuppressive cell populations, regulatory cytokines, and metabolic barriers-are examined in the context of their roles in mediating therapeutic resistance. Biomarkers predictive of treatment response-including PD-L1 expression and tumor mutational burden-are summarized, integrating recent clinical and translational evidence. We conclude by outlining future research directions focused on overcoming therapeutic resistance, refining predictive and prognostic biomarkers, and developing next-generation immunotherapies to improve clinical outcomes for patients.