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Cell surface receptors play vital roles in cancer growth and metastasis. Integrin αvβ3 is overexpressed in various cancer cells and interacts with different growth factors to stimulate cancer progression. Thyroid hormone binds to αvβ3 to activate signal transduction and cell proliferation. However, thyroxine (T₄) deaminated analogue, tetraiodothyronine (tetrac), competes for the binding on integrin and inhibits cancer cell growth and metastasis. The current study investigated the pathogenic role of integrin αvβ3 and the potential of a novel therapeutic strategy targeted to integrin αvβ3. Pathogenetic studies of clinical samples revealed integrin αvβ3 cross-talked with EGFR and downstream signal transduction networks affected by thyroid hormone and EGF related to the progression of cholangiocarcinoma malignancy. Thyroxine and EGF stimulated PD-Ligand 1 (PD-L1) expression and cancer growth in cholangiocarcinoma. The thyroxine-induced PD-L1 accumulated in the nuclei and colocalized with p300. Alternatively, EGF increased cytosolic PD-L1 and nuclear accumulation of β-catenin. Targeting integrin αvβ3 with lipo-tetrac and its Dox-derivative induced anti-proliferation in vitro and in the xenografted animal model. Our research provides a fundamental understanding of the therapeutic role of integrin αvβ3 and the potential therapeutic approach in cholangiocarcinoma treatment.