The Lactate-Lactylation Axis as a Metabolic-Epigenetic Framework for Therapeutic Adaptation in Esophageal Squamous Cell Carcinoma.

Therapeutic failure in esophageal squamous cell carcinoma (ESCC) can arise as tumor cells and their microenvironment adapt to sustained treatment pressure. The lactate-lactylation axis may connect altered metabolism with adaptive treatment responses through changes in protein and chromatin regulation. However, how this axis contributes to therapeutic adaptation in ESCC and how its mechanistic evidence should be interpreted across different biological contexts remain incompletely defined. Here, we review lactate sources, the regulatory landscape of lysine lactylation, and emerging evidence linking this axis to heterogeneous treatment responses in ESCC. Studies in ESCC implicate several lactylation-related processes in therapeutic adaptation. These include poly(ADP-ribose) polymerase 1 (PARP1) K654 lactylation in DNA damage responses, signal transducer and activator of transcription 3 (STAT3) K631 and nudix hydrolase 21 (NUDT21) K23 lactylation in programmed cell death susceptibility, and the NIPA-like domain containing 1 (NIPAL1)-histone H3 lysine 18 lactylation(H3K18la) and hypoxia-inducible factor 1α (HIF-1α) K172la axes in immune microenvironment remodeling. The strength of evidence differs across individual mechanisms. Several site-specific lactylation events have been identified in ESCC models or patient-derived specimens and supported by functional validation, whereas the role of lactylation-associated pathways in predicting immunotherapy response requires further clinical investigation. Therefore, the lactate-lactylation axis is best viewed as an emerging metabolic-epigenetic network that connects cellular metabolic states with adaptive treatment phenotypes rather than as a universal resistance mechanism. Integrating longitudinal clinical cohorts, multi-omics profiling, and mechanistic studies will be critical for defining how lactate-lactylation signatures may support patient stratification and precision therapeutic strategies in ESCC.