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

<strong>Background:</strong> Malignant melanoma, the 19th most prevalent cancer globally, is the primary cause of mortality attributed to cutaneous malignancies. Ginsenoside 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. <strong>Purpose:</strong> This study aimed to investigate the influence of CK on cGAS-STING pathway in melanoma, particularly its effects on apoptosis and the immune microenvironment, with the ultimate goal of impeding melanoma growth. <strong>Study design:</strong> In the present study, we used a subcutaneous hormonal tumor model in homozygous mice to investigate whether ginsenoside CK has an inhibitory effect on melanoma growth. <strong>Methods:</strong> The effect of ginsenoside CK on melanoma cell apoptosis was analyzed by flow cytometry, immunohistochemistry, H&amp;E staining, protein immunoblotting, and RT-qPCR was used to observe the effect of ginsenoside CK on melanoma cytokines. The effects of ginsenoside CK on cGAS-STING pathway in melanoma cells were investigated by protein immunoblotting, immunofluorescence, flow cytometry and molecular docking. <strong>Results:</strong> Our findings demonstrate that ginsenoside 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. <strong>Conclusion:</strong> Ginsenoside 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.