Objective:

To summarize current evidence linking the lactate-lactylation axis to tumor radioresistance, with emphasis on metabolic adaptation, DNA damage repair, and immunosuppressive remodeling of the tumor microenvironment.

Approach:

• Literature Search Strategy: The review was prepared from literature searches of PubMed, Web of Science, Scopus, and Google Scholar using terms related to lactate, lactylation, radiotherapy, and related mechanisms.

Key Findings:

• Lactate metabolism and protein lactylation are regulators of tumor adaptation to irradiation.
• Lactate is linked to DNA damage repair, redox buffering, and clonogenic survival in irradiated tumor models.
• Lactylation may regulate chromatin accessibility and immune remodeling.
• RNA-processing mechanisms related to lactate remain insufficiently validated in radiotherapy models and are discussed primarily as emerging hypotheses.

Interpretation:

The review emphasizes the need to differentiate between established, emerging, and hypothetical mechanisms in understanding lactate's role in radioresistance.

Limitations:

• Evidence strength varies across metabolic, epigenetic, immune, and RNA-regulatory mechanisms.
• RNA-processing mechanisms are primarily discussed as emerging hypotheses rather than established drivers.

Conclusion:

The review highlights unresolved mechanistic questions and future directions for integrating various approaches to improve radiosensitization.