BACKGROUND & AIMS: ICC is a malignant tumor that originates from the intrahepatic bile ducts with insidious symptoms and a poor prognosis. Early diagnosis methods and therapeutic targets are urgently needed for ICC. METHODS: We utilized a comprehensive set of analytical techniques to elucidate the role and mechanisms of DCDC2 in ICC. Our study included protein microarrays, transcriptome analysis, functional assays, immunofluorescence, dual-luciferase reporter assays, as well as xenograft models and humanized PBMC models. RESULTS: Our study demonstrates that elevated levels of anti-DCDC2 autoantibodies in the serum of ICC patients indicate its potential utility as a diagnostic biomarker. Comprehensive in vitro and in vivo analyses reveal that DCDC2 promotes ICC proliferation, metastasis, and immune evasion. Mechanistically, DCDC2 stabilizes ENO1, resulting in enhanced AKT phosphorylation and increased expression of FGL1. Notably, elevated FGL1 levels significantly impair CD8(+) T cell functionality via the FGL1-LAG3 axis. CONCLUSION: Our findings position anti-DCDC2 autoantibody as a promising diagnostic biomarker for ICC, associated with poor prognostic outcomes, and elucidate its critical role in tumor growth and immune evasion through its interaction with ENO1.