Isoforsythiaside Impeded Osteosarcoma Progression and Elicited Anti-Tumor Immunity by Suppressing LSD1 Expression

Osteosarcoma (OS) is a highly malignant tumor arising from mesenchymal tissues and manifests with bone and joint pain and a local mass. OS patients typically have a poor prognosis and no significant improvement has been achieved over the last few decades. Isoforsythiaside (IFA), a monomer compound originating from a commonly-used Chinese medicinal herb named Fructus Forsythiae, recently was reported to show potential anti-tumor activity in breast tumors. However, the role of IFA in OS progression and therapy, especially in immune therapy, remains largely unexplored. Cell proliferation, migration, and colony formation abilities of OS cells were analyzed using CCK-8 detection, wound-healing assay, colony formation assay, and nude mouse xenotransplantation models. Immunohistochemical staining (IHC) was utilized to assess the expression level of Ki67 and the number of CD8+ T cells in tumor tissue. In addition, quantitative real-time polymerase chain reaction (qPCR) and cell transfection were performed to explore the mechanism of IFA anti-tumor action. The results of the in vitro and in vivo experiments revealed that IFA inhibited growth, migration, and invasion in OS cells. Notably, histone lysine-specific demethylase 1 (LSD1, also named KDM1A) downregulation was found to play a vital role in IFA inhibition on OS progression. Finally, the in vivo experimental results demonstrated that IFA promoted CD8+ T cell infiltration and enhanced anti-PD1 therapeutic effect by downregulating LSD1. Our findings in this study suggested that downregulating LSD1 exhibited remarkable activity in inhibiting OS progression and enhanced anti-PD1 therapeutic effect. The combined application of IFA and anti-PD1 may be a promising treatment strategy for OS.