{
  "abstract": "Background Lymph node metastasis (LNM) is a major determinant of poor prognosis in intrahepatic cholangiocarcinoma (ICC), occurring in approximately 30–45% of patients undergoing lymphadenectomy. However, the mechanisms driving LNM, including tumor-intrinsic factors and dynamic immune microenvironment changes in metastatic lymph nodes, remain poorly understood. A detailed characterization of these processes is critical for developing therapeutic strategies for ICC patients with LNM.Methods We conducted single-cell RNA sequencing (scRNA-seq) on tumor and lymph node samples from 10 ICC patients with or without LNM, including primary tumors (T), metastatic lymph nodes (MLN), tumor-draining lymph nodes without tumor colonization (DLN), and normal lymph nodes (NLN). Key findings were further validated in bulk RNA sequencing data from an independent ICC cohort.Results Consensus non-negative matrix factorization (cNMF)-based clustering of tumor cells identified an estrogen response module that was enriched in primary tumors with LNM and positively correlated with lacto- and neolacto-series glycosphingolipid biosynthesis pathways. The fucosyltransferase FUT2 emerged as a key downstream effector, upregulated in the estrogen-response cluster and associated with poor prognosis. METAFlux analysis showed that tumor cells associated with LNM exhibited increased uptake of glucose, galactose, and fucose, indicating elevated fucosylation. CD15 was identified as a potential fucosylated product mediating tumor adhesion to lymphatic endothelial cells through interactions with E-, L-, and P-selectins, thereby facilitating LNM. Consistently, Rap1 signaling, involved in cell adhesion and migration, was activated in lymphatic endothelial cells. Compared with DLNs, MLNs exhibited profound structural and immune remodeling, characterized by enrichment of matrix cancer-associated fibroblasts (mCAFs) and angiogenesis-associated myeloid cells, accompanied by reduced proportions of T and B cells. In contrast, DLNs were enriched with activated plasmacytoid dendritic cells (pDCs), which were recruited by inflammatory CAFs (iCAFs) via the CXCL12–CXCR4 axis, suggesting a potential suppressive role for tumor colonization.Conclusions During lymph node metastasis of ICC, estrogen signaling enhances tumor cell adhesion to lymphatic vessels through activation of the FUT2-mediated fucosylation pathway, thereby promoting metastatic dissemination. Concurrently, tumor-driven immunosuppressive niches in LNs, dominated by mCAFs and pro-tumorigenic myeloid cells, further facilitate tumor colonization. These findings suggest potential therapeutic targets for inhibiting lymph node metastasis and personalized treatment strategies for ICC patients with LNM.",
  "authors": [
    {
      "affiliations": [
        "The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Jiale Chen"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Yujun Liu"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Yuting Hong"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Shuo Wang"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital, Sun Yat-sen University, China"
      ],
      "name": "Zhihang Chen"
    }
  ],
  "title": "IDDF2026-ABS-0175 Estrogen-driven FUT2-dependent fucosylation promotes lymph node metastasis and immunosuppressive remodeling in intrahepatic cholangiocarcinoma",
  "uid": "9eb85bba-21c5-5963-ab84-9923c9ad8525"
}