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Risk stratification and multi-omics reveal RAD51 inhibition as a radiosensitizing strategy in triple-negative breast
Ran An1,2,3,4, Jianming Li1,2,3,4, Tianhui Liu1,2,3,4
1Department of Breast Imaging, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
Frontiers in Immunology
|August 12, 2026
Summary
Triple-negative breast cancer (TNBC) shows varied radiotherapy response due to heterogeneity. Targeting RAD51 may restore radiosensitivity and reverse immunosuppression in aggressive tumors.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Triple-negative breast cancer (TNBC) is aggressive and heterogeneous.
- Radiotherapy response in TNBC is variable and poorly understood.
- Molecular determinants of TNBC radiosensitivity require elucidation.
Purpose of the Study:
- To profile cell-type-specific radiosensitivity in TNBC.
- To define molecular subtypes and develop a prognostic model for TNBC.
- To identify therapeutic targets for improving radiotherapy response in TNBC.
Main Methods:
- Integrated single-cell and bulk transcriptomic analysis.
- Consensus clustering for molecular subtyping.
- Random survival forest (RSF) model construction and validation.
- Dependency Map (DepMap) analysis for target identification.
- In vitro and in vivo functional validation of RAD51.
- Immunofluorescence and protein analysis for immune microenvironment assessment.
Main Results:
- Fibroblasts, macrophages, and proliferative cells exhibit radioresistance.
- Two TNBC subtypes identified: Cluster A (immunosuppressive, radioresistant) and Cluster B (immune-active, favorable survival).
- RSF model accurately stratified patient risk, correlating high-risk with immune-desert tumors.
- RAD51 identified as a key dependency; its knockdown sensitized TNBC to irradiation.
- RAD51 inhibition combined with radiotherapy suppressed tumor growth and remodeled the tumor microenvironment (TME).
- Combination therapy enhanced CD8+ T cell infiltration, M1 macrophage repolarization, and PD-L1 expression.
Conclusions:
- Integrative multi-omics study reveals TNBC radioresistance mechanisms.
- RSF model offers robust risk stratification for TNBC patients.
- RAD51 is a promising therapeutic target to enhance radiosensitivity and overcome immunosuppression in high-risk TNBC.
