Alcohol-Induced Metabolic Stress Sensed by m6A-Modified ChREBP Drives Immune Evasion in Esophageal Carcinogenesis.

UNLABELLED: Chronic alcohol consumption is an established risk factor for esophageal squamous cell carcinoma (ESCC). Elucidating the underlying mechanisms linking metabolic stress to esophageal carcinogenesis could help identify prevention and treatment strategies. Through a transancestry meta-analysis encompassing more than 200,000 individuals from East Asia, we identified a germline variant (rs1051921 C>T) at the MLXIPL locus [encoding carbohydrate-responsive element-binding protein (ChREBP)] that markedly elevated ESCC risk among alcohol drinkers. Functionally, the risk allele facilitated N6-methyladenosine (m6A) modification of ChREBP transcripts, enhancing their stability through recognition by the m6A reader YTHDF1. Alcohol further potentiated this regulatory axis by promoting ACSS2-mediated conversion of acetate into acetyl-CoA and increasing H3K27ac enrichment at the promoters of key m6A regulators. Increased ChREBP expression activated the transcription factor ATF3, which triggered endoplasmic reticulum stress and epithelial-mesenchymal transition, thereby conferring anoikis resistance. In parallel, ATF3 promoted an immunosuppressive tumor microenvironment through the upregulation of PD-L1 and VEGFA, leading to the exclusion of CD8+ T cells and the expansion of granulocytic myeloid-derived suppressor cells. In vivo intervention via ATF3 knockdown, anti-PD-L1 treatment, or pharmacologic perturbation of ChREBP-related metabolism with metformin or an ACSS2 inhibitor significantly suppressed ESCC progression and restored intratumoral CD8+ T-cell infiltration. These findings establish ChREBP as an alcohol-sensitive metabolic-epitranscriptomic switch that integrates genetic susceptibility with immune evasion to drive esophageal carcinogenesis.

SIGNIFICANCE: Alcohol-responsive m6A-ChREBP signaling links genetic susceptibility to metabolic stress and immune evasion in esophageal cancer, revealing actionable targets for risk stratification, prevention, and immunometabolic intervention in high-risk drinkers.