Genomic, transcriptomic, proteomic, phosphoproteomic and microbiomic studies were performed for the clinical tissue samples from Chinese intrahepatic cholangiocarcinoma (iCCA) patients. The genetic characteristics of iCCA were revealed by analyzing the genetic information. It was found that the samples contained aflatoxin-induced gene mutation "fingerprint", and the mutation "fingerprint" was associated with tumor genesis, proliferation and immunosuppression. Correlation analysis of somatic chromatin copy number alterations showed that cis/trans effects of CNA caused changes in mRNA, protein and phosphorylation. Pathway enrichment analysis showed that cis/trans effects were significantly correlated with changes in some protein and related pathways. In addition, the related signal of genetic mutations showed that TP53, KRAS, BAP1 and IDH1/2 gene mutations could affect downstream related protein and phosphorylation abundance, thus affecting the occurrence and development of disease. It was found that TP53/KRAS dual mutations may promote iCCA metastasis through the integrin-FAK /SRC pathway, resulting in poorer prognosis. In conjunction with the drug target database, it was found that higher expression of the target protein in gene mutation-related patient group could be used for personalized treatment, which was validated by patient-derived primary cancer cell lines. The iCCA patients were divided into four subgroups by proteomic analysis, and these four subgroups have specific characteristics. Four subgroup-specific protein biomarkers from each proteomic subgroup were identified by omic data dimension reduction analysis. And these four biomarkers were further validated in this and another independent patient cohort by immunofluorescence staining. Two potential protein biomarkers of iCCA, SLC16A3 protein and HKDC1 protein, were identified by clinical risk model analysis of proteomic data. Further analysis and verification showed that these two proteins were associated.