Objective:

To develop a glycolysis-associated biomarker for radiotherapy sensitivity in head and neck squamous cell carcinoma (HNSC).

Approach:

• Data Analysis: Analyzed gene expression and clinical data from 491 HNSC patients and single-cell RNA sequencing to assess glycolysis activity.
• Radiosensitivity Index Development: Developed a glycolysis-associated radiosensitivity index (RI) using Cox regression analysis of glycolysis-related genes.
• Immune Microenvironment Profiling: Analyzed immune microenvironment profiles and therapeutic responses using ssGSEA, CIBERSORT, TIDE, and pRRophetic.
• In Vitro Validation: Conducted in vitro experiments to validate glycolytic activity and radiosensitivity in HNSC cell lines.

Key Findings:

• Low glycolytic activity correlates with improved overall survival in HNSC patients post-radiotherapy.
• High glycolytic activity is associated with radio-resistance.
• The RI successfully stratified patients into radiosensitive (RS) and radio-resistant (RR) groups.
• RS tumors showed higher immune cell infiltration and lower TIDE scores, indicating better immunotherapy response.
• RR tumors exhibited increased sensitivity to chemotherapy agents, including platinum and EGFR/HER2 inhibitors.
• Single-cell RNA sequencing revealed high-glycolysis tumors had diminished immune cell infiltration, particularly CD8+ T cells.

Interpretation:

Glycolytic activity significantly influences radiotherapy sensitivity in HNSC.

Limitations:

• The study relies on retrospective data, which may introduce biases.
• Further validation in larger, independent cohorts is necessary.

Conclusion:

The findings highlight the potential of the glycolysis-based RI as a predictive biomarker for radiotherapy outcomes in HNSC.