# miR-181d coordinates homologous recombination and anti-tumor immune responses in glioblastoma

## TL;DR

This study shows that miR-181d helps control glioblastoma resistance to treatments and boosts immune responses against the cancer.

## Contribution

miR-181d is identified as a master regulator linking DNA repair and immune responses in glioblastoma.

## Key findings

- miR-181d suppresses RAD51, reducing resistance to TMZ and radiation in glioblastoma.
- Restoring miR-181d reverses DNA repair-mediated resistance and boosts anti-tumor immunity.
- miR-181d delivery in mice improves radiation response and immune memory against glioblastoma.

## Abstract

Master regulatory microRNAs (miRNAs) are characterized by their ability to coordinate distinct yet interconnected pathways to drive transitions in cell states. In this study, we identify miR-181d as a master regulatory miRNA that coordinates acquired resistance and anti-tumoral immunity in glioblastoma, the most prevalent form of adult primary brain cancer. Profiling of miR-181d targets revealed RAD51, an essential gene for homologous recombination (HR). miR-181d binding to RAD51 mRNA, which suppresses RAD51 expression, was abolished by mutating the miR-181d binding site in the RAD51 3′ UTR. The radiation-sensitizing and HR-suppressing effects of miR-181d were epistatic to RAD51in vitro and in vivo. Temozolomide (TMZ) treatment induced cross-resistance to radiation and acquired resistance to TMZ; both forms of resistance were eliminated by RAD51 silencing or miR-181d transfection. Finally, the exogenous introduction of miR-181d in an immunocompetent murine glioblastoma model before radiation treatment induced anti-glioblastoma immune memory. These results support consideration for miR-181d-based glioblastoma therapy.

•miR-181d suppresses BER and HR to control glioblastoma resistance to TMZ and IR•Loss of miR-181d elevates RAD51, promoting both TMZ resistance and cross-resistance to IR•Restoring miR-181d reverses DNA repair-mediated therapeutic resistance•miR-181d delivery enhances anti-GBM immune memory and improves radiation response

miR-181d suppresses BER and HR to control glioblastoma resistance to TMZ and IR

Loss of miR-181d elevates RAD51, promoting both TMZ resistance and cross-resistance to IR

Restoring miR-181d reverses DNA repair-mediated therapeutic resistance

miR-181d delivery enhances anti-GBM immune memory and improves radiation response

Therapeutics; Immune response; Cancer