A proteome-derived inflammatory epithelial-myeloid state is associated with adverse outcome in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is molecularly heterogeneous, and the cellular basis of adverse bulk-omics states is often unclear. We examined whether a proteome-derived prognostic score reflects an inflammatory malignant epithelial-myeloid state. A score derived from Fudan proteomics was evaluated without refitting in MSKCC and UKF proteomic cohorts, same-source Fudan mRNA, and two external RNA-seq cohorts. Bulk signature analyses and four ICC-filtered single-cell RNA-seq datasets were used for biological localization. Marker-defined myeloid states and expression-supported ligand-receptor inference were examined as secondary analyses. A higher inflammatory epithelial-myeloid (iEM) score was associated with worse overall survival in Fudan proteomics (hazard ratio [HR] per standard deviation, 2.59; 95% confidence interval [CI], 2.06–3.26; P < 0.001), MSKCC (HR, 1.80; 95% CI, 1.32–2.46; P < 0.001), UKF (HR, 1.42; 95% CI, 1.11–1.83; P = 0.006), and all three transcriptomic datasets. Single-cell projection localized the score most consistently to myeloid cells and, where evaluable, malignant epithelial cells. Within myeloid cells, FCN1/IL1B monocyte-like and SPP1/TREM2 tumor-associated macrophage states showed positive score enrichment in all four datasets, whereas CD1C conventional dendritic cells showed the opposite direction. Computational communication analysis nominated ANXA1-FPR1 and HLA-F-LILRB2 as candidate epithelial-to-myeloid axes. The iEM score links adverse outcome with inflammatory epithelial and myeloid states across public ICC datasets. Cross-modality projection and ligand-receptor findings remain associative and require spatial, protein-level, and experimental validation.