Ginsenoside CK inhibits melanoma growth by promoting apoptosis and targeting cGAS-STING pathway to regulate the immune microenvironment

Malignant melanoma, the 19^th most prevalent cancer globally, is the primary cause of mortality attributed to cutaneous malignancies. Ginsenoside compound K (CK), a rare ginsenoside renowned for its potent medicinal properties and established safety profile, is widely employed in the treatment and prevention of various diseases. This study aimed to investigate the influence of CK on cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in melanoma, particularly its effects on apoptosis and the immune microenvironment, with the ultimate goal of impeding melanoma growth. In the present study, we used a subcutaneous hormonal tumor model in homozygous mice to investigate whether CK has an inhibitory effect on melanoma growth. The effect of CK on melanoma cell apoptosis was analyzed by flow cytometry, immunohistochemistry, hematoxylin and eosin staining, protein immunoblotting, and RT-qPCR were used to observe the effect of CK on melanoma cytokines. The effects of CK on cGAS-STING pathway in melanoma cells were investigated by protein immunoblotting, immunofluorescence, flow cytometry and molecular docking. The findings demonstrate that CK effectively suppresses melanoma cell proliferation. Molecular docking analysis revealed a binding energy of –6.59 kcal/mol between CK and STING, indicating the potential of CK as a targeted regulator of STING. Mechanistically, CK induces apoptosis in melanoma cells through the Caspase pathway and enhances STING-mediated regulation of the immune microenvironment via the cGAS-STING pathway, thereby inhibiting melanoma growth. Notably, our study provides the first evidence that CK acts as an immune checkpoint agonist, elevating T lymphocyte levels within tumors. CK promotes apoptosis through the Caspase pathway, regulates the cGAS-STING pathway, promotes the production of IFN-β and chemokines by the nucleus, and promotes the infiltration of T-cells in the tumor microenvironment, thus achieving the inhibition of melanoma.