6-Gingerol (6-G) is the main bioactive component in Ginger (Zingiber officinale Roscoe). The aim of this study was to explore the contribution of macrophage polarization in 6-G-associated anti-
cancer effects. In a
urethane-induced lung carcinogenic model, lung
carcinogenesis was positively correlated with macrophage (F4/80+) infiltration in lung interstitial in the control group. Furthermore, higher numbers of
arginase+/F4/80+ M2 cells than iNOS+/F4/80+ M1 cells were observed in interstitial macrophages. Moreover, macrophage depletion by
liposome-encapsulated
clodronate (LEC) could significantly prevent lung
carcinogenesis, whereas
pexidartinib promoted lung
carcinogenesis. After 6-G treatment, lung
carcinogenesis was ameliorated with increased M1 macrophages and decreased M2 macrophages in the lung interstitial. ELISA showed that the levels of IFN-γ and
IL-12 increased and the levels of
IL-10 and TGF-β1 decreased in the alveolar cavity compared to those in the control group. Unexpectedly, the
carcinogenesis-preventing efficacy of 6-G was promoted in LEC-treated mice, but completely aborted in
pexidartinib-treated mice. In the in vitro experiment, 6-G reset the IL-4-induced arginase+ M2 cells toward iNOS+ M1 cells and exhibited reduced levels of
arginase 1 and ROS and elevated levels of
L-arginine and NO. LEC and nor-NOHA selectively suppressed M2 macrophages but had a negligible effect on M1 macrophages, whereas
pexidartinib decreased both M2 and M1 macrophages. The iNOS+ macrophage-promoting efficacy of 6-G was increased by LEC, but was completely eliminated by pretreatment with
pexidartinib or nor-NOHA. M2 macrophage-resetting efficacy of 6-G was confirmed in a Lewis
lung cancer allograft model. This study indicated a reprogramming effect of 6-G as an
arginase inhibitor on
tumor supporting macrophages.