Bladder cancer (BLCA) is one of the most prevalent malignant tumors of the urinary tract worldwide, second only to prostate cancer. However, the mechanisms by which BLCA cells regulate immune-related molecules to escape immune cell attack, as well as how to optimize immunotherapy strategies, remain unresolved. This study focuses on the induction of Programmed Cell Death-Ligand 1 (PD-L1) expression by HDAC inhibitors (HDACi) and its molecular mechanisms, while also exploring the regulation of miRNAs. Additionally, we investigate the potential of combining HDACi with immune checkpoint inhibitors (ICIs) as a therapeutic strategy for offering a novel strategy for clinical immunotherapy.

Human bladder cancer cell lines (5637, T24, and UMUC3) were obtained from the Bioresource Collection and Research Center (BCRC). Western blotting and real-time reverse transcription-polymerase chain reaction (RT-PCR) were performed to analyze protein and mRNA expression levels, respectively. The luciferase reporter assay was used to measure PD-L1 gene transcription activity. The effects of HDACi on bladder cancer immunotherapy were further evaluated using a mouse orthotopic bladder cancer model.

The results indicate that HDACi induces PD-L1 expression in bladder cancer cells through the JAK2/STAT3 and MEK/ERK signaling pathways. Additionally, hsa-miR-193a-5p was implicated in the post-translational regulation of PD-L1 expression by HDACi.

This study demonstrates that the HDACi influence the immune escape mechanism of bladder cancer, and this result provided more detail on the function of treating bladder cancer.