From Bench to Bladder: The Rise in Immune Checkpoint Inhibition in the Treatment of Non-Muscle Invasive Bladder Cancer.

Non-muscle invasive bladder cancer (NMIBC) represents a significant clinical challenge due to its high recurrence rate and need for frequent monitoring. The current treatment modality is bacillus Calmette-Guérin (BCG) therapy combined with chemotherapy after transurethral resection of the bladder tumor (TURBT), which is highly effective in most patients. Yet, the cancer becomes resistant to these treatments in 30-40% of patients, necessitating the need for new treatment modalities. In the cancer world, the development of immune checkpoint inhibitors that target molecules, such as programmed cell death protein-1 (PD-1), its ligand, PD-L1, and Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), have revolutionized the treatment of many cancer types. PD-1/PD-L1 and CTLA-4 are shown to be upregulated in NMIBC in certain circumstances. PD-1/PD-L1 interactions play a role in immune evasion by suppressing T cell activity within the tumor microenvironment (TME), while the binding of CTLA-4 on T cells leads to downregulation of the immune response, making these pathways potential immunotherapeutic targets in NMIBC. This review seeks to understand the role of these therapies in treating NMIBC. We explore the cellular and non-cellular immune landscape in the TME of NMIBC, including Tregs, T effector cells, macrophages, B cells, and relevant cytokines. We also discuss the biological role of PD-1/PD-L1 and CTLA-4 while covering the rationale for these immunotherapies in NMIBC. Finally, we cover key clinical trials that have studied these treatments in NMIBC clinically. Such a study will be helpful for urologists and oncologists to manage patients with NMIBC more effectively.