Integrative multi-omics profiling identifies a lactylation-associated, metabolically active, and immunosuppressive subtype of colon adenocarcinoma

Background Histone lactylation, a lactate-derived post-translational modification, bridges metabolic activity and gene regulation. However, its molecular mechanisms and clinical significance in colon adenocarcinoma (COAD) remain poorly characterized.Methods We conducted multi-omics analyses on TCGA and GTEx datasets, characterizing lactylation-associated genes via differential expression, enrichment, mutation profiling, and immune deconvolution. Subsequent prognostic modeling, transcriptional network construction, and drug sensitivity predictions assessed their biological and clinical relevance.Results We identified 133 lactylation-associated genes and constructed an eight-gene prognostic signature (CCNA2, CALD1, CSRP2, MSN, RPS23, PSME3IP1, VIM, and SRRM2). High-score tumors exhibited poorer overall survival, enriched glycolytic, cell-cycle, and epithelial-mesenchymal transition pathways, and increased TP53 and KRAS mutations. Single-cell and protein-level analyses localized key genes to endothelial and macrophage compartments. Single-cell and protein-level analyses localized key genes primarily to endothelial and macrophage compartments. Furthermore, high-score tumors displayed reduced cytotoxic T- and NK-cell infiltration, increased M0/M2 macrophages, elevated TIDE scores, and lower immunophenoscores, indicating profound immune suppression. They also demonstrated higher stemness and reduced sensitivity to 5-fluorouracil, oxaliplatin, and sorafenib.Conclusions Lactylation-associated transcriptional programs delineate a metabolically active, immunosuppressed COAD subtype characterized by adverse prognoses and therapeutic resistance. This lactylation-based score serves as a clinically relevant biomarker and a promising target for combined metabolic–epigenetic and immunotherapeutic interventions.