Lactylation drives tumor microenvironment remodeling and immune evasion in esophageal cancer revealed by multiomics and single cell transcriptomics

Objectives: This study aimed to investigate the prognostic value of lactate metabolism-related genes (LMRGs) in esophageal cancer (EC), exploring their roles in tumor microenvironment (TME) remodeling, immunotherapy response, and potential therapeutic targeting. Methods: Multi-omics analysis integrated bulk RNA-seq (TCGA, GEO) and single-cell RNA-seq (scRNA-seq) data. Differential expression, WGCNA, and LASSO regression were employed to identify prognostic LMRGs. Immune infiltration, drug sensitivity (GDSC), and pathway enrichment (GSEA/GSVA) analyses were performed. scRNA-seq delineated lactate-high cell populations in TME. Results : A 9-gene LMRG signature (ABRACL, CXCL8, TRIB3, DNMT3B, PHYHD1, KIF4A, CDKN3, LMNB2, PCLAF) was established, stratifying EC patients into high/low-risk groups with distinct survival (p<0.001). High-risk patients exhibited immunosuppressive TME (elevated Mast cells, follicular T cells), activated mTORC1/NF-κB pathways, and poorer immunotherapy response. Key genes (DNMT3B, CXCL8) correlated with EMT and neutrophil recruitment. Drug screening nominated Alisertib and Nutlin-3a as potential therapies. Conclusion: The LMRG model elucidates lactate-driven EC progression and immune evasion, offering prognostic biomarkers and therapeutic targets. Combining lactate modulation with targeted therapy may overcome treatment resistance.