Histone lactylation-driven IGF2BP3 promotes intrahepatic cholangiocarcinoma progression via SPP1/CD44-dependent macrophage polarization.

The tumor microenvironment is a critical regulator of cancer progression. Histone lactylation, a novel post-translational modification, has emerged as a key player in various tumors and is closely linked to macrophage polarization within the immune tumor microenvironment. Here, we delineated the signaling axis through which histone lactylation, specifically H3K18la, orchestrates crosstalk between intrahepatic cholangiocarcinoma cells and the tumor microenvironment (TME). Cleavage Under Target and Tagmentation analysis revealed an enrichment of H3K18la at the promoter of the N6-methyladenosine reader protein insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3), enhancing its transcription. IGF2BP3 stabilizes the mRNA of the key factor secreted phosphoprotein 1 (SPP1), thereby promoting its secretion. Single-cell RNA sequencing indicated that tumor-derived SPP1 promoted intrahepatic cholangiocarcinoma (iCCA) progression by acting on macrophages via the SPP1/CD44 axis, inducing M2 polarization and migration to shape an immunosuppressive tumor microenvironment. Furthermore, using clinically relevant patient-derived organoids, xenograft models, and immunocompetent mouse models, we demonstrated that a glycolysis inhibitor synergizes with the first-line chemotherapeutic agent gemcitabine, significantly enhancing its therapeutic efficacy. These findings deliver a new exploration and important supplement of metabolic reprogramming, epigenetic regulation, and tumor immune microenvironment, and provide a new strategy for improving clinical efficacy of gemcitabine in iCCA by inhibiting histone lactylation.