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

Abstract

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.