miR-125b-5p sensitizes colorectal cancer to anti-PD-L1 therapy by decreasing TNFR2 expression on tumor cells.

The microRNA 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 by reducing the expression of tumor necrosis factor receptor 2 (TNFR2) on regulatory T cells. 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, in which we noted a regression of 20% to 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.