Exosomal miR-184 facilitates bladder cancer progression by targeting AKR1C3 and inducing immune escape via IRF2-CXCL10 axis

Abstract

Currently, the molecular mechanisms underlying bladder cancer progression remain unclear. Immune checkpoint inhibitors (ICIs) have been used to treat bladder cancer, but their efficacy is limited. Exosomes, which play a critical role in cell communication, can alter the tumor microenvironment. Therefore, it is essential to investigate the impact of bladder cancer exosomes on the tumor microenvironment. Our research demonstrates a significant up-regulation of miR-184 in exosomes derived from bladder cancer cells. miR-184 promotes bladder cancer cell proliferation in vitro and facilitates tumor growth in mice by targeting the 3’ UTR of AKR1C3 mRNA. Additionally, miR-184 targets IRF2 mRNA, reducing its transcriptional inhibition on CXCL10. This process induces the expression of CXCL10, which promotes the infiltration of CD8+ T cells into the tumor. However, these infiltrating T cells become exhausted. In summary, our study reveals that bladder cancer-derived exosomes deliver miR-184, which targets AKR1C3, contributing to bladder carcinogenesis and development. We also investigate how the IRF2-CXCL10 pathway induces T cell exhaustion and leads to immune escape. This research provides new insights into the immunotherapy of bladder cancer, highlighting potential molecular targets for more effective treatment strategies.