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

TL;DR

This paper reviews recent immunotherapy advances for bladder cancer, including immune checkpoint inhibitors and CAR-T therapies, and discusses mechanisms, clinical trials, and future directions.

Contribution

The paper provides a comprehensive review of novel immunotherapies and resistance mechanisms in bladder cancer treatment.

Findings

Immune checkpoint inhibitors and CAR-T therapies are transforming bladder cancer treatment.

Combination strategies with ICIs and other therapies are being actively explored.

Tumor microenvironment factors play key roles in mediating resistance to immunotherapy.

Abstract

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.

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