N-亚硝胺消毒副产物（NAs-DBP）已被充分证明其在食管癌发生中的作用。然而，在暴露于 NAs-DBP 的背景下，肿瘤内微生物在食管鳞状细胞癌 (ESCC) 中的作用尚未得到很好的探索。在这里，多组学整合揭示了牙周杆菌（Fp）作为“促进剂”在癌组织中高度富集，并促进食管鳞癌上皮间质转化（EMT）样亚型的形成。我们证明 Fp 通过其独特的 FadAL 粘附素有效驱动脂肪酸的从头合成、迁移、侵袭和 EMT 表型。然而，N-亚硝基甲基苄胺上调 FadAL 的转录水平。从机制上讲，免疫共沉淀与质谱联用表明 FadAL 与 FLOT1 相互作用。此外，FLOT1 激活 PI3K-AKT/FASN 信号通路，导致甘油三酯和棕榈酸 (PA) 积累。创新地，酰基-生物素交换的结果表明，FadAL 介导的 PA 积累增强了 Wnt3A 在保守半胱氨酸残基 Cys-77 上的棕榈酰化，并促进 Wnt3A 膜定位和 β-连环蛋白易位到细胞核中，进一步激活 Wnt3A/ β-连环蛋白轴和诱导 EMT 表型。因此，我们提出了高度异质性肿瘤微环境中的“微生物群-癌细胞亚群”相互作用模型。这项研究揭示了 Fp 驱动 ESCC 的机制，并将 FadAL 确定为 ESCC 的潜在诊断和治疗靶点。

N-Nitrosamine disinfection by-products (NAs-DBPs) have been well proven for its role in esophageal carcinogenesis. However, the role of intratumoral microorganisms in esophageal squamous cell carcinoma (ESCC) has not yet been well explored in the context of exposure to NAs-DBPs. Here, the multi-omics integration reveals F. periodonticum (Fp) as "facilitators" is highly enriched in cancer tissues and promotes the epithelial mesenchymal transition (EMT)-like subtype formation of ESCC. We demonstrate that Fp potently drives de novo synthesis of fatty acids, migration, invasion and EMT phenotype through its unique FadAL adhesin. However, N-nitrosomethylbenzylamine upregulates the transcription level of FadAL. Mechanistically, co-immunoprecipitation coupled to mass spectrometry shows that FadAL interacts with FLOT1. Furthermore, FLOT1 activates PI3K-AKT/FASN signaling pathway, leading to triglyceride and palmitic acid (PA) accumulation. Innovatively, the results from the acyl-biotin exchange demonstrate that FadAL-mediated PA accumulation enhances Wnt3A palmitoylation on a conserved cysteine residue, Cys-77, and promotes Wnt3A membrane localization and the translocation of β-catenin into the nucleus, further activating Wnt3A/β-catenin axis and inducing EMT phenotype. We therefore propose a "microbiota-cancer cell subpopulation" interaction model in the highly heterogeneous tumor microenvironment. This study unveils a mechanism by which Fp can drive ESCC and identifies FadAL as a potential diagnostic and therapeutic target for ESCC.