Metastatic microenvironment of extrahepatic cholangiocarcinoma

Extrahepatic cholangiocarcinoma (eCCA) is a highly malignant tumor with a propensity for metastasis, reflected in its estimated 5-year survival rate of 11%. Metastasis greatly impairs the effectiveness of cancer therapies and increases cancer-related deaths. Therefore, gaining an understanding of the complex metastatic process is essential for development of effective treatments. Metastasis progression involves remodeling of the tumor microenvironment (TME) and the formation of premetastatic niches (PMNs), facilitating the migration and survival of tumor cells from the primary site to distant locations. As the eCCA progresses, immune cells, fibroblasts, and endothelial cells in the TME are gradually converted to a tumor-supportive phenotype, coordinating tumor metastasis through intercellular interactions. Recent studies have confirmed that bile, a body fluid in close contact with eCCA, is also involved in the formation of supportive TME and tumor metastasis. On the contrary, primary tumors construct PMNs conducive to cancer cell colonization in distant organs before metastatic tumor formation through paracrine effects. This review aimed to summarize the mechanisms by which TME and PMNs drive eCCA metastasis, current treatment strategies for metastatic eCCA, and prospects for future research.