Abstract 7: Lipid-driven oxidative phosphorylation fuels lymph node colonization by esophageal tumor cells

Abstract Lymph node (LN) metastasis is a pivotal step in the progression of esophageal squamous cell carcinoma (ESCC) and is associated with poor clinical outcomes. Despite its significance, the mechanisms underlying the early colonization of LNs by tumor cells remain insufficiently understood. In this study, we utilized a human xenograft model of spontaneous LN metastasis and performed single-cell RNA sequencing to analyze the transcriptomes of tumor cells from primary tumors and LN metastases. A rare subset of metastasis-initiating cells (MICs) with stem-like characteristics was identified as critical drivers of LN metastasis. These MICs exhibited a unique metabolic adaptation, relying on fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) to survive in the lipid-enriched LN microenvironment. Additionally, nuclear factor erythroid 2-related factor 2 (NRF2) was found to play a key role in maintaining redox balance and supporting the metabolic resilience of MICs during metastatic progression. This study underscores the importance of FAO-driven OXPHOS and NRF2-regulated redox homeostasis in LN metastasis and highlights these pathways as promising targets for therapeutic intervention in ESCC. Citation Format: Shanshan Li, Baifeng Zhang, Cuicui Huang, Yuying Zhao, Stephanie Ma, Xinyuan Guan. Lipid-driven oxidative phosphorylation fuels lymph node colonization by esophageal tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7.