# Non‐Coding RNAs in Breast Cancer Radioresistance: Mechanisms, Functional Roles and Translational Potentials

## TL;DR

Non-coding RNAs help breast cancer cells resist radiation, and targeting them with RNA-based therapies could improve treatment, though delivery challenges remain.

## Contribution

This review systematically summarizes ncRNA mechanisms in breast cancer radioresistance and highlights translational RNA-based therapeutic strategies.

## Key findings

- ncRNAs influence radioresistance through DNA repair, cell cycle, and tumor microenvironment pathways.
- RNA-based therapies like ASOs and CRISPR show potential but face delivery and stability issues.
- Nanocarriers and multi-omics approaches may enhance ncRNA-based radiosensitization strategies.

## Abstract

Breast cancer remains the most prevalent malignancy among women, and radiotherapy plays a pivotal role in reducing local recurrence and improving prognosis. However, the emergence of radioresistance in a subset of patients significantly compromises treatment efficacy, underscoring the need for a deeper understanding of the underlying molecular mechanisms. In recent years, non‐coding RNAs (ncRNAs) have emerged as key regulators of gene expression and have garnered increasing attention for their roles in mediating radioresistance in breast cancer. This review systematically summarises the major molecular mechanisms by which ncRNAs contribute to breast cancer radioresistance, including cell cycle regulation, DNA damage repair, programmed cell death (e.g., apoptosis, autophagy and ferroptosis), oxidative stress response, tumour microenvironment remodelling and maintenance of cancer stem cell properties. On the translational front, RNA‐based therapeutic approaches—including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), miRNA mimics and CRISPR/Cas9—offer promising avenues for radiosensitisation, yet face substantial clinical hurdles. These include immune activation, poor delivery specificity, intracellular trafficking barriers and limited stability. Advances in chemical modifications and nanoparticle‐based delivery systems—such as redox‐responsive nanocarriers—have shown potential in enhancing the efficacy and safety of ncRNA‐targeted therapies. Despite encouraging progress, clinical translation remains constrained by a lack of methodological standardisation, insufficient high‐quality clinical data, limited biomarker reliability, suboptimal target selection and unresolved safety concerns. Future efforts should prioritise optimisation of delivery platforms, validation of multi‐ncRNA biomarker panels in large, multicentre cohorts and integration of multi‐omics data to reconstruct comprehensive regulatory networks, ultimately accelerating the clinical deployment of ncRNA‐based radiosensitisation strategies.

Non‐coding RNAs (ncRNAs) regulate breast cancer radioresistance via cell cycle, DNA repair and tumour microenvironment pathways. Targeting ncRNAs (e.g., HOTAIR and miR‐155) with RNA‐based therapies (ASOs and CRISPR) shows promise but faces delivery challenges. Advances in nanocarriers and multi‐omics integration may overcome barriers to clinical translation of ncRNA radiosensitisation strategies.