Gypenosides inhibit melanoma proliferation, migration and enhance the anti-tumor immunity of CD8+ T cells via ETV5/PD-L1 signaling.

BACKGROUND: Melanoma is a highly aggressive cancer that often creates a profoundly immunosuppressive tumor microenvironment and tends to invade and metastasize early in the disease process. Gypenosides have been reported to exhibit anti-melanoma activity, yet its underlying mechanisms remain incompletely understood. The objective is to assess the role of gypenosides in anti-melanoma and to further investigate its pharmacological effects. METHODS: A systematic evaluation of the anti-melanoma efficacy and safety of gypenosides was established by in vitro and in vivo experiments. Transcriptome sequencing was used to screen potential molecular targets, and co-culture and flow cytometry were applied to explore the effects of gypenosides, aiming to elucidate the underlying mechanisms. RESULTS: Both in vitro and in vivo experiments have observed that gypenosides, as well as their active monomers gypenoside-XLIX and gypenoside-LI, significantly inhibit melanoma cell proliferation by inducing G0/G1 cell cycle arrest, and inhibit migration through downregulating MMP2/MMP9. RNA-sequencing combined with gene expression perturbation identified ETV5 as the key mediator of the anti-tumor activity of gypenosides. Additionally, gypenosides downregulate the expression of PD-L1 via ETV5 in tumor cells, thereby promoting the activation of tumor-infiltrating CD8+ T cells and enhancing CD8+ T cell-mediated anti-melanoma immunity. In mouse tumor models, gypenosides demonstrate potent efficacy in inhibiting melanoma growth and lung metastasis, and exhibit a favorable safety profile. CONCLUSION: Gypenosides and its active monomers gypenoside-XLIX and gypenoside-LI inhibit the proliferation and migration of melanoma, suppress the upregulation of ETV5-mediated increase in PD-L1 expression, and enhance the anti-tumor immunity of CD8+ T cells and promote the release of cytokines. These findings indicate that gypenosides may have valuable applications in the clinical treatment of melanoma and provide a useful theoretical basis.