Lycorine suppresses hepatocellular carcinoma via the reprogramming of myeloid and epithelial cells

Background Hepatocellular carcinoma (HCC) is an aggressive malignancy associated with an immunosuppressive tumor microenvironment (TME), which contributes to resistance to therapy. Lycorine, a natural alkaloid, has demonstrated anticancer potential, but its effects on HCC remain insufficiently explored. Purpose This study aimed to systematically assess the impact of lycorine on HCC and elucidate its underlying mechanisms of action. Study design In vivo orthotopic HCC mouse models were employed, incorporating high-dimensional single-cell techniques to comprehensively analyze the effects of lycorine on the TME. Methods Mice bearing orthotopic HCC tumors were treated with lycorine at doses of 10 or 20 mg/kg for 14 days. Tumor progression was assessed by measuring tumor weight. The immune landscape was examined using cytometry by time of flight (CyTOF), and cellular heterogeneity was evaluated via single-cell RNA sequencing (scRNA-seq). Cell-cell communication networks were reconstructed through CellChat analysis. Results Lycorine treatment significantly reduced tumor burden and modulated cytokine expression profiles. CyTOF analysis revealed that lycorine reprogrammed the immune landscape, enhancing macrophage and neutrophil infiltration while decreasing PD-L1 expression on neutrophils. scRNA-seq analysis indicated that lycorine regulated specific cell subpopulations, including malignant epithelial cells, Notch2 + neutrophils, and Spp1 + macrophages. Cell-cell communication analysis identified the regulation of the Mif-(Cd74+Cd44/Cxcr4) signaling axis as a key underlying mechanism. Conclusion Lycorine remodels the HCC TME through coordinated actions on malignant epithelial cells and immune populations, notably neutrophil and macrophage subpopulations. These findings support the potential development of lycorine-based combination therapies for HCC.