IFI27 enhances bladder cancer immunotherapy response by modulating regulatory T cell enrichment

Bladder cancer (BCa) is the 10th most prevalent cancer globally. Neoadjuvant therapy has become the standard treatment for muscle-invasive bladder cancer, yet the pathologic complete response rate for patients is only approximately 35%. However, the mechanisms underlying neoadjuvant therapy resistance in bladder cancer patients remain unclear. We collected two sets of paired bladder cancer specimens before and after neoadjuvant therapy, and performed RNA sequencing. The findings revealed a significant decrease in IFI27 expression levels in the post-neoadjuvant therapy group compared to samples collected before treatment, suggesting that IFI27 may play a role in resistance to neoadjuvant combination therapy. IFI27, a member of the interferon-alpha (IFN-α) inducible gene family, influences the efficacy of immune checkpoint blockade therapy. Further analysis demonstrated that IFI27 is predominantly expressed in the cytoplasm of bladder cancer cells and exhibited low expression levels in bladder cancer tissues and cell lines. Subsequently, we investigated the inhibitory effects of IFI27 on bladder cancer proliferation, migration, epithelial-mesenchymal transition, and lymph node metastasis. Additionally, in a mouse model, PD-1Ab immunotherapy was found to upregulate IFI27 while downregulating the protein level of FOXP3, a key transcription factor for regulatory T cells. Flow cytometric analysis further demonstrated that IFI27 inhibits bladder cancer progression by suppressing regulatory T cell infiltration and enhancing anti-tumor immune responses. In conclusion, these findings establish IFI27 as a promising molecular marker for improving the efficacy of immunotherapy in bladder cancer and offer valuable insights into strategies for enhancing immunotherapy sensitivity.