Abstract 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 trans-ancestry meta-analysis encompassing more than 200,000 individuals from East Asia, we identified a germline variant (rs1051921 CT) at the MLXIPL locus (encoding 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-driven acetyl-CoA synthesis and increasing H3K27ac enrichment at 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 upregulation of PD-L1 and VEGFA, leading to exclusion of CD8+ T cells and expansion of granulocytic myeloid-derived suppressor cells. In vivo intervention via ATF3 knockdown, anti-PD-L1 treatment, or pharmacological 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.
X et al. (Fri,) studied this question.