Rad51 at the crossroads: bridging DNA repair, tumorigenesis, and immune regulation

September 24, 2025 — Today, a research team from Beijing Chest Hospital, Capital Medical University, published a review article titled "Rad51 at the Crossroads: Bridging DNA Repair, Tumorigenesis, and Immune Regulation" in the journal *Med Research*. This article provides a comprehensive analysis of the multifaceted functions of the Rad51 protein—the core executor of DNA homologous recombination repair—in cancer biology, with a specific focus on its pivotal role in connecting DNA damage repair, tumor progression, and immune regulation.

Rad51 is a key protein for cells to repair DNA double-strand breaks. The review first systematically elaborates on the core mechanisms of Rad51 in the DNA damage response, including how it assembles into nucleoprotein filaments and performs homology search and strand invasion under the influence of numerous regulatory factors to achieve high-fidelity DNA repair. However, Rad51 is a double-edged sword. Its overexpression in various tumors (such as breast cancer, ovarian cancer, and lung cancer), while initially contributing to genomic stability, more frequently leads to resistance to chemotherapy, radiotherapy, and PARP inhibitors, and is associated with poor patient prognosis.

The highlight of the article lies in revealing Rad51's function beyond DNA repair—the regulation of tumor immunity. The review points out:

Dysregulation of Rad51 function can alter the immunogenicity of tumor cells by affecting the cGAS-STING innate immune pathway.

Rad51 is involved in regulating the expression of Programmed Death-Ligand 1 (PD-L1), a key molecule in tumor immune escape. The DNA damage response pathway (e.g., ATR/Chk1) acts synergistically with inflammatory signals to jointly upregulate PD-L1, thereby inhibiting T cell function.

In tumors with homologous recombination repair deficiencies (e.g., BRCA mutations), the use of PARP inhibitors may influence PD-L1 expression by activating the cGAS-STING pathway, providing a rationale for combining PARP inhibitors with immune checkpoint blockade therapy.

Based on these findings, the authors outlook therapeutic strategies targeting Rad51, including the development of small-molecule Rad51 inhibitors and monoclonal antibodies, and discuss their potential for combination with existing immunotherapies, chemotherapy, and radiotherapy to overcome tumor drug resistance and enhance anti-tumor immune responses.

"A deep understanding of Rad51's role in the tumor immune microenvironment is crucial for developing new combination treatment strategies," said Professor Teng Ma, the corresponding author of the review from Beijing Chest Hospital, Capital Medical University. "Our work aims to provide new perspectives and targets for future precision cancer immunotherapy."

This review serves as a valuable resource for researchers engaged in cancer biology, DNA repair, and tumor immunotherapy.