A TMED3-governed disulfidptosis-related diagnostic signature reveals tumor microenvironment remodeling in intrahepatic cholangiocarcinoma

作者：Qiao W, He Y, Li J, Liu X, Zhang L, Bai X, Wang Y, Tang J · 发表于：Frontiers in immunology · 年份：2026 · DOI：10.3389/fimmu.2026.1858117 · 被引用次数：56 · 研究领域：Disulfidptosis、Cholangiocarcinoma、Tumor Microenvironment、Bile Duct Neoplasms、Biomarkers, Tumor、Humans、Gene Expression Regulation, Neoplastic、Prognosis、Transcriptome

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and limited treatment options. Disulfidptosis, a novel cell death pathway driven by disulfide bond accumulation, has emerged as a potential mechanism in cancer biology; however, its role in ICC remains unclear. METHODS: We integrated single-cell RNA sequencing (GSE138709) with bulk transcriptomic datasets (TCGA-CHOL, GSE107943, GSE32225) to systematically characterize the ICC cellular landscape. Analyses included CNV inference, stemness scoring, disulfidptosis activity assessment, and cell-cell communication profiling. A diagnostic model was constructed using LASSO-logistic regression with 10-fold cross-validation and validated in independent cohorts. TME characterization, survival analysis, and drug-target screening were also performed. Experimental validation included HPA immunohistochemistry, qRT-PCR, and functional assays following TMED3 knockdown. RESULTS: Seven major cell types were identified, with malignant cholangiocytes exhibiting high aneuploidy (74%), elevated stemness, upregulated disulfidptosis activity, and extensive communication via SPP1-CD44 and IGFBP3-TMEM219 networks. A five-gene signature (TMED3, TMEM184B, MAPK13, MFSD10, GRB7) demonstrated robust diagnostic performance. Survival analysis showed borderline prognostic value for TMED3 (adjusted HR = 2.37, P = 0.073), while TMEM184B emerged as an independent prognostic factor (adjusted HR = 4.79, P = 0.028). P...