Tumor-derived Exosomal LINC01812 Induces M2 Macrophage Polarization to Promote Perineural Invasion in Cholangiocarcinoma

M2 macrophages play a critical role in the tumor microenvironment of invasive solid tumors. They are closely associated with perineural invasion (PNI) and are often linked to poor prognosis. In this context, tumor-derived exosomes serve as important mediators of intercellular communication. However, the relationship between tumor cell-induced M2 macrophages and PNI in cholangiocarcinoma remains unexplored. In this study, we utilized multiplex immunofluorescence and transcriptomic sequencing to demonstrate the upregulation of LINC01812 in cholangiocarcinoma tissues and its positive correlation with M2 macrophage infiltration. Exosomal lncRNA sequencing, exosome uptake experiments, RNA pull-down assays, and mass spectrometry analysis demonstrated that macrophages can internalize exosomal LINC01812 and promote the M2 phenotype in cholangiocarcinoma cells. Additionally, Transwell and in vitro cocultures with the dorsal root ganglia confirmed that the tumor microenvironment significantly enhances the nerve infiltration of cholangiocarcinoma cells via M2 macrophages. The findings of this study indicate that exosomes containing LINC01812 derived from cholangiocarcinoma can induce M2 macrophage polarization and facilitate nerve infiltration, thereby providing new potential therapeutic targets for managing PNI in cholangiocarcinoma.