Deciphering the Metastatic Nexus: Molecular Drivers and Therapeutic Frontiers in Cholangiocarcinoma Lymph Node Dissemination.

Lymph node metastasis (LNM) is a major determinant of staging and outcome in cholangiocarcinoma (CCA), yet its mechanisms, biomarkers, anatomical heterogeneity, and treatment evidence remain insufficiently integrated. This review develops an LNM-centered framework in which lymphatic invasion, lymphangiogenesis, genomic alterations and metabolic reprogramming, and reciprocal tumor microenvironment remodeling interact to shape CCA LNM by enabling lymphatic entry, dissemination, immune evasion, tumor-cell survival, and nodal colonization. A subtype-aware synthesis distinguishes small-duct-type and large-duct-type intrahepatic CCA, positions the latter as a biological bridge to perihilar and distal CCA, and maps subtype-associated lymphangiogenic, matrix-remodeling, metabolic, stromal, and immune programs. Translationally, serum ANGPTL4 and exosomal TTN-AS1 are prioritized as candidate adjuncts to preoperative radiologic nodal assessment and CA19-9, whereas tissue ITGB6 represents a comparatively well-characterized candidate for postoperative or biopsy-integrated LNM risk assessment. For node-positive CCA requiring systemic therapy, PD-1/PD-L1 blockade plus gemcitabine-cisplatin provides the first-line backbone. Additional opportunities include intensified chemoimmunotherapy and antiangiogenic combinations, postoperative and locoregional multimodal treatment, genotype-directed or cellular therapies, and mechanism-informed targeting of chemoresistance, oncogenic and lymphangiogenic signaling, stromal and immune niches, and metabolic adaptation. Epigenetic circuitry and post-transcriptional regulation represent emerging regulatory layers, while microbiome-immune interactions provide testable hypotheses for LNM. We propose spatial multi-omics across paired primary tumors, pathologically negative tumor-draining nodes, and metastatic nodes, integrated with pathology-validated liquid biopsy, to identify where metastatic competence emerges and how nodal niches are conditioned. Together, this mechanism-to-clinic synthesis provides a subtype-aware roadmap for biomarker validation, LNM-specific endpoints, and rational therapeutic intervention.