<p>Tumor necrosis factor-α-induced protein-8 (TNFAIP8/TIPE) like-2 (TIPE2), a critical member of the TIPE protein family, has been characterized as a tumor suppressor across multiple malignancies. Its functional significance in cholangiocarcinoma pathogenesis remains poorly defined. To address this knowledge gap, we established a discovery cohort of 218 cholangiocarcinoma patients and an independent validation cohort of 95 cases. The expression of TIPE2 was explored via immunohistochemistry (IHC). The correlation between patients’ clinical parameters including overall survival and TIPE2 expression were evaluated. A nomogram including TIPE2 expression was also constructed and validated to for prognostic prediction. The effect and related mechanisms of TIPE2 on the malignant behaviors of cholangiocarcinoma was investigated both in vitro, in silico, and in vivo. The two cohorts demonstrated that TIPE2 expression was decreased in cholangiocarcinoma tissues, and TIPE2 expression was closely related with tumor stage and the prognosis of cholangiocarcinoma patients. Nomogram including TIPE2 expression could predict the prognosis of cholangiocarcinoma patients effectively. TIPE2 suppressed the proliferation, migration and invasion capacities of cholangiocarcinoma cells, and inhibited tumor growth in vivo. Mechanistically, TIPE2 suppressed the trafficking of integrin αvβ6 via targeting RAC1, which subsequently suppressed the progression of cholangiocarcinoma. Through comprehensive clinical cohorts and functional investigations, the present study identified TIPE2 as a clinically significant prognostic biomarker and revealed its potential role in regulating integrin-mediated oncogenic processes in cholangiocarcinoma. Therapeutic enhancement of TIPE2 expression emerges as a promising precision medicine strategy for cholangiocarcinoma management.</p>