Molecular biomarkers for diagnosis, prognosis, precision therapy, and immunotherapy in cholangiocarcinoma, cHCC-CCA, and HCC.

Primary liver cancers include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), combined hepatocellular-cholangiocarcinoma (cHCC-CCA), and rarer hepatic malignancies. Their biomarker landscapes differ substantially. HCC has many approved systemic therapies, yet most are still selected through clinical context, liver function, tumor burden, and treatment line. By contrast, iCCA and broader biliary tract cancers (BTCs) have fewer patients but multiple treatment-directing genomic alterations, including FGFR2 fusions or rearrangements, IDH1 mutations, HER2 positivity, BRAF V600E, NTRK or RET fusions, and microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status. cHCC-CCA adds a diagnostic layer because lineage classification and sampling adequacy influence whether HCC-based or BTC-based evidence is more relevant. This review organizes biomarkers by the treatment decision they are expected to support. It covers curative intent and locoregional risk stratification, molecularly guided systemic therapy, immune-state assessment, dynamic monitoring, resistance reassessment, and translational readiness. Across these settings, biomarker value depends on clinical action, evidence maturity, assay feasibility, and timing. The review separates decision-ready markers, trial-enrichment tools, monitoring assays, and mechanistic signatures.