miR-133b induces antitumor immunity in cervical cancer through modulating CMTM6/PD-L1 axis.

Abstract

Immune evasion mediated by the PD-L1 pathway remains a major hurdle in the effective treatment of cervical cancer (CC). While microRNAs (miRNAs) are known to critically regulate host immune responses, their specific roles in modulating the immunosuppressive microenvironment in CC remain largely elusive. Therefore, this study aims to elucidate the scope, clinical relevance, and mechanistic actions of the novel miR-133b/CMTM6/PD-L1 axis in cervical cancer immune evasion. Through a comprehensive series of in vitro and in vivo assays, we evaluated the expression and function of miR-133b, CMTM6, and PD-L1 in CC tissues and cell lines. Our results revealed that miR-133b is significantly downregulated in CC, which strongly correlates with poor patient prognosis. Mechanistically, miR-133b directly targets CMTM6, thereby suppressing PD-L1 expression. In clinical CC tissues, miR-133b levels were negatively correlated with both CMTM6 and PD-L1. Utilizing an immune-competent murine syngeneic model, we demonstrated that miR-133b overexpression profoundly inhibited tumor growth. This tumor suppression was accompanied by enhanced intra-tumoral infiltration of CD4⁺ and CD8⁺T cells and an attenuated presence of myeloid-derived suppressor cells (MDSCs). Furthermore, co-culture experiments revealed that miR-133b-overexpressing CC cells significantly increased IFN-γ release, decreased IL-10 secretion, and attenuated T cell apoptosis effects that were mechanistically dependent on the inhibition of the CMTM6/PD-L1 axis. In conclusion, our findings establish miR-133b as a critical tumor suppressor and immune modulator in cervical cancer. By deciphering the miR-133b/CMTM6/PD-L1 regulatory network, this work provides a novel mechanistic perspective on CC immune evasion, suggesting that targeting this axis holds significant promise as a therapeutic strategy to reverse the immunosuppressive microenvironment and enhance anti-tumor immunity.