Cholangiocarcinoma-derived SPP1 drives tumor progression by inducing macrophage chemotaxis and M2 polarization

Cholangiocarcinoma, a hepatobiliary malignancy, has a poor prognosis and treatment resistance. This study integrated spatial transcriptome and conditional knockdown models to explore the tumor microenvironment (TME) regulatory mechanism. We found that macrophages were located at the boundary between cholangiocarcinoma and normal tissue. Cholangiocarcinoma - secreted SPP1 induced blood monocytes to migrate toward the tumor tissue and polarize into M2 macrophages through the CD44 - PI3K - AKT pathway. In vitro and in vivo experiments confirmed this process. Macrophages polarized by SPP1 promoted tumor proliferation through the TGF - β/P - SMAD2/P - SMAD3 pathway. Targeting SPP1 or TGF - β inhibited tumor progression. This study reveals the bidirectional regulatory mechanism of the SPP1 - TGF - β axis in cholangiocarcinoma, providing new perspectives for developing combined therapies targeting the tumor - immunity interaction network.