Hypoxia, a low-oxygen state, is a common feature of solid tumors. MCP1 (CCL2) is a small cytokine that is closely related to hypoxia and has a positive effect on tumor development. Hypoxia causes resistance to various treatments for solid tumors and the evasion of cancer immune surveillance by lymphocytes. Natural killer (NK) cells are innate lymphocytes that play an important role in cancer development, particularly in the liver. First, it was found that the incubation of HCC in hypoxia (2-5% O) significantly increased the production of several inflammatory cytokines, including MCP1, compared to that of normal oxygen (20% O). Subsequently, blocking MCP1 with an anti-MCP1 antibody in HCC cultures inhibited the growth and migration of HCC cells in vitro and in vivo. This was associated with a decrease in the expression of HIF-1α/STAT3 in HCC under hypoxia. Furthermore, blocking MCP1 in HCC cell cultures under hypoxia significantly increased the chemotaxis and activation of NK-92 cells against HCC cells. MCP1 blockade in HCC cell cultures under hypoxia induced a shift in NK cells to the CD56 population and an increase in the expression of the activation receptors NKG2D and NKp44. In conclusion, modulation of MCP1 could enhance NK activity against hypoxic HCC cells.