# Glycolysis-related radiosensitivity signature for predicting radiotherapy response in breast cancer

## TL;DR

This study shows that glycolytic activity in breast cancer patients affects radiotherapy response and identifies a four-gene signature to predict treatment outcomes.

## Contribution

A novel glycolysis-related radiosensitivity signature is developed to predict radiotherapy efficacy in breast cancer.

## Key findings

- Low glycolysis in breast cancer patients correlates with better radiotherapy response.
- A four-gene signature effectively stratifies patients into radiosensitive and radioresistant groups.
- Radiosensitive patients show an active immune landscape and better outcomes with high PD-L1 expression.

## Abstract

This study investigates the influence of glycolytic activity on the efficacy of radiotherapy in breast cancer (BRCA) patients, aiming to develop a glycolysis-related radiosensitivity signature to predict radiotherapy efficacy.

We categorized BRCA patients into low and high glycolysis groups using ssGSEA analysis based on 200 glycolysis-related genes. Univariate and multivariate Cox regression analyses, were used to construct a radiosensitivity signature. Immune cell infiltration and pathway enrichment analyses were conducted using ESTIMATE and CIBERSORT methods. The TIDE algorithm and pRRophetic algorithm were employed to predict responses to radiotherapy. Radioresistant BRCA cells were examined using CCK-8 assay. Key genes identified in the radiosensitivity signature were validated in vitro by qRT-PCR. Seahorse assay was used to evaluate cellular glycolytic capacity.

Our analyses revealed that patients in the low-glycolysis group exhibited enhanced sensitivity to radiotherapy, suggesting that glycolytic activity is a critical determinant of radiotherapy. Subsequently, we developed a four-gene radiosensitivity signature that effectively stratified patients into radiosensitive (RS) and radioresistant (RR) groups. Survival analysis revealed that radiotherapy significantly improves outcomes in the RS group but not in the RR group. Immune infiltration analysis indicated that the RS group correlates with an active immune landscape, as evidenced by lower TIDE scores and higher responsiveness to immune checkpoint inhibitors. Notably, patients in the RS group with high PD-L1 expression showed significantly better outcomes, associated with increased immune cell infiltration. In vitro validation using MCF-7 and radioresistant MCF-7/IR cell lines confirmed that radioresistant MCF-7/IR cells exhibit increased glycolytic activity.

Our study establishes glycolytic activity as a promising predictor of radiotherapy efficacy in BRCA patients and develops a novel radiosensitivity signature with potential clinical utility in guiding personalized treatment strategies.