Natural killer (NK) cells are lymphocytes of the innate immune system that play a crucial role in tumor immune surveillance. Accumulated data indicated that NK cells in the tumor microenvironment often display a suppressed function. However, the mechanism is not clear.In this study, the effects and relative mechanisms of malignant pleural effusion (MPE) from patients with lung cancer on NK cells were researched.MPE and peripheral blood (PB) samples were collected from patients with lung cancer. The cytotoxic activity of CD56(dim) NK cells in PB and MPE mononuclear cells was analyzed by flow cytometry.It was observed that the percentages of total NK cells and a CD56(dim) NK subset in MPE reduced accompanying impaired cytotoxic activity compared with that in paired PB. Cell-free MPE treatment reduced both the proportion and cytotoxic activity of CD56(dim) NK cells in PB from healthy donors. The suppression effects were not based on soluble carcinoembryonic antigen and the inhibitory cytokines interleukin-10 and transforming growth factor-β1, but were dependent on the factor with a molecular weight >100 kDa.These results demonstrated that native soluble carcinoembryonic antigen does not suppress the activity of NK cells, and an unknown factor with a molecular weight >100 kDa plays a critical role in the impairment of CD56(dim) NK cells in MPE, which might lead to tumor progression.