The lactate-lactylation axis in tumor radioresistance: metabolic, epigenetic, and immune mechanisms with emerging links to RNA regulation.

Radiotherapy remains a cornerstone treatment for solid tumors, but its efficacy is frequently limited by intrinsic and acquired radioresistance. Increasing evidence indicates that lactate metabolism and protein lactylation are not merely by-products of glycolysis, but context-dependent regulators of tumor adaptation to irradiation. In irradiated tumor models, lactate-associated metabolic rewiring has been linked to DNA damage repair, redox buffering, and clonogenic survival. Other mechanisms, including chromatin remodeling, immune suppression, and RNA-level regulation, should be interpreted according to their evidence strength, ranging from direct radiotherapy evidence to mechanistic inference from related cancer or immune models. Beyond its metabolic functions, lactate provides a biochemical context for lysine lactylation, an emerging post-translational and epigenetic modification that may regulate chromatin accessibility, stress-responsive transcription, selected DNA damage response proteins, and immune remodeling. Current evidence also suggests possible intersections with post-transcriptional regulation, including m6A-dependent RNA stability and RNA-binding protein activity. However, these RNA-processing-related mechanisms remain insufficiently validated in radiotherapy models and are discussed here primarily as an emerging, hypothesis-generating layer rather than as an established driver of radioresistance. This review summarizes 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. We also discuss therapeutic strategies targeting this axis, including MCT and LDH inhibitors, oxidative phosphorylation blockade, indirect modulation of lactylation-associated machinery, and lactate-depleting nanoplatforms. Finally, we highlight unresolved mechanistic questions and future directions for integrating metabolic, epigenetic, immune, and cautiously framed RNA-processing approaches to improve radiosensitization.