Cigarette smoke-induced sphingosine-1-phosphate drives cancer-associated fibroblasts activation and esophageal cancer carcinogenesis

The metabolic impact of cigarette smoke on tumor microenvironment remodeling remains poorly defined. Here, we identify a missense variant in ACER1 that confers elevated risk of esophageal squamous cell carcinoma (ESCC) specifically among smokers, based on a gene-smoking interaction analysis involving 10,716 cases and 12,637 controls. Functional assays demonstrate that the risk allele synergizes with nicotine and benzo[a]pyrene to enhance sphingosine-1-phosphate (S1P) biosynthesis and secretion in ESCC epithelial cells. Integrated single-cell RNA sequencing, spatial proteomics, and multiplex immunofluorescence analyses across multi-stage ESCC samples reveal that this ACER1-driven sphingolipid reprogramming promotes the activation of myofibroblastic cancer-associated fibroblasts (myCAFs). Mechanistically, epithelial-secreted S1P engages the S1PR3-ERK-AKT signaling cascade in fibroblasts, promoting a pro-tumorigenic stromal state. Pharmacological inhibition of S1PR3 markedly suppresses ESCC growth in vivo . These findings uncover a critical gene-environment interaction driving pro-tumorigenic microenvironmental remodeling in esophageal tumorigenesis and highlight a metabolic vulnerability for early detection and therapeutic intervention.