Enhanced antitumor activity of gemcitabine by polysaccharide-induced NK cell activation and immune cytotoxicity reduction in vitro/vivo

•The polysaccharide SEP is a D-glucan and can activate NK cells.•SEP effectively enhances antitumor activity of gemcitabine against liver cancer.•SEP activates NK cells through stimulating NKG2D/DAP10/Akt signaling pathway.•Gemcitabine-induced immune cytotoxicity is attenuated by SEP suppressing ROS secretion. The polysaccharide SEP has been reported to activate NK and T cells via TLR2/4. Here, the combination of gemcitabine (GEM) and SEP against HepG-2 was investigated. SEP apparently enhanced antitumor activity of gemcitabine against liver cancer through stimulating NKG2D and DAP10/Akt pathway to activate NK cells. The NKG2D upregulation could improve the sensitivity of NK-92 cells targeting to its ligand MICA expressed on HepG-2 cells. Meanwhile, GEM up-regulated MICA expression and attenuated soluble MICA secretion through inhibiting ADAM10 expression, which in turn enhanced the cytotoxicity of NK-92 cells against cancer cells. SEP remarkably enhanced GEM antitumor activity with an inhibitory rate of 79.1% in an H22-bearing mouse model. Moreover, SEP reversed atrophy and apoptosis caused by GEM in both spleen and bone marrow through suppressing ROS secretion in vivo. The data indicated that the combination of SEP and GEM is a potential chemo-immunotherapy strategy for liver cancer treatment clinically.