Alcohol-Induced Metabolic Stress Sensed by m6A-Modified ChREBP Drives Immune Evasion in Esophageal Carcinogenesis - PubMed
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- #Immune Evasion
- #ChREBP
- #Esophageal Carcinogenesis
- Chronic alcohol consumption is a known risk factor for esophageal squamous cell carcinoma (ESCC).
- A germline variant (rs1051921 C>T) at the MLXIPL locus (encoding ChREBP) increases ESCC risk in alcohol drinkers.
- The risk allele enhances m6A modification of ChREBP transcripts, stabilizing them via YTHDF1, with alcohol boosting this by promoting ACSS2-driven acetyl-CoA synthesis.
- Increased ChREBP expression activates ATF3, triggering ER stress, epithelial-mesenchymal transition, and anoikis resistance.
- ATF3 also promotes an immunosuppressive tumor microenvironment by upregulating PD-L1 and VEGFA, excluding CD8+ T cells and expanding granulocytic MDSCs.
- Interventions like ATF3 knockdown, anti-PD-L1 treatment, or drugs targeting ChREBP-related metabolism (e.g., metformin) suppress ESCC progression and restore CD8+ T-cell infiltration.