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.