J Leukoc Biol. 2025 May 20:qiaf059. doi: 10.1093/jleuko/qiaf059. Online ahead of print.
ABSTRACT
The micro-RNA miR-125b-5p, recognized as a tumor suppressor, has demonstrated the ability to curb the proliferation of various types of cancer cells. Our latest research has revealed that miR-125b-5p also impedes the proliferation and functionality of CD4+Foxp3+ regulatory T cells (Tregs) by reducing the expression of tumor necrosis factor receptor Ⅱ (TNFR2) on Tregs. To explore the potential of miR-125b-5p to suppress tumor growth by targeting TNFR2 on cancer cells, we overexpressed the levels of miR-125b-5p in mouse colorectal cancer cells. Our findings showed that the overexpression of miR-125b-5p significantly suppressed the proliferation, migration, and invasiveness of TNFR2-expressing cancer cells. This was further supported by in vivo observations, where we noted a regression of 20-30% of tumors in immunocompetent mice that had been treated with miR-125b-5p-overexpressing cells. Remarkably, when combined with anti-PD-L1 therapy, the regression rate increased dramatically, with over 85% of mice showing a 2- to 3-fold enhancement in tumor regression. This synergistic effect was attributed to the miR-125b-5p-mediated increase in cytotoxic CD8+ T cells. In conclusion, our study suggests that miR-125b-5p, by inhibiting TNFR2 expression in colorectal cancer cells, can enhance the effectiveness of anti-PD-L1 immunotherapy. This is achieved by modulating anti-tumor immune responses. The potential of miR-125b-5p to boost the efficacy of immunotherapies in clinical settings is a promising avenue for future therapeutic development.
PMID:40391464 | DOI:10.1093/jleuko/qiaf059