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

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. 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. 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. 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.