Abstract 2274: Cigarette smoke-induced sphingosine-1-phosphate drives cancer-associated fibroblasts activation and esophageal cancer carcinogenesis.

Abstract 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. Citation Format: Xinying Yue, Jialing Ma, Zifei Yang, Yutong Wu, Qianqian Su, Lina Song, Miaoxin Pan, Dongxu Li, Qingyi Liu, Shasha Liu, Yueping Li, Shaokai Zhang, Siyuan Wang, Li Zhang, Ni Zhang, Wei Ping, Catherine C. Wong, Dongxin Lin, Chen Wu, Jiang Chang. Cigarette smoke-induced sphingosine-1-phosphate drives cancer-associated fibroblasts activation and esophageal cancer carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2274.