Zingerone enhances the antitumor activity of attenuated Salmonella-mediated cancer immunotherapy by promoting tumor infiltration by host immune cells

Bacteria-mediated cancer immunotherapy (BCI) suppresses tumor progression in two ways: the bacteria themselves kill tumor cells, and they elicit robust host immune responses. However, this does not eradicate tumors completely or prevent metastasis. Therefore, the immune responses elicited by BCI must be backed up by other therapies such as chemotherapy. Zingerone has anticancer activity and modulates T cell-mediated immune responses. Here, we examined the antitumor effects of zingerone/BCI combination therapy. We show that that zingerone 1) enhances St.Delta ppGpp-mediated antitumor effects, but reduces survival of tumor-colonizing bacteria by promoting recruitment of tumor-infiltrating neutrophils; 2) amplifies St.Delta ppGpp-mediated immune responses by stimulating tumor infiltration by macrophages, natural killer cells, and CD4(+) and CD8(+) T cells; and 3) enhances St.Delta ppGpp-mediated macrophage phagocytosis, leading to tumor eradication. These findings suggest that the zingerone/St.Delta ppGpp combination has synergistic antitumor effects, making it a promising approach to cancer immunotherapy.