Figure 1. The varied roles of NK cells during metastasis.

NK cell activity varies in different organs and at different stages of metastasis. Contributing to the different functions of NK cells are the changes within the cancer cell that occur at each stage. Initially NK cells control metastasis by targeting highly invasive metastatic cells that express K14 and lack MHC class I molecules (14). However, as cancer cells change their shape, features, and molecular composition during the process of metastasis, they can alter the function of NK cells as a mode of immune escape. As polyclonal clusters of metastatic cancer cells disseminate and circulate, they display increased epithelial behavior (55) and recruit neutrophils that shield them from NK cell attack (69). During colonization of a distal organ, increases in TGF-β (61) and PGE₂ (65) in the tumor microenvironment (TME) inactivate NK cells. Dormant cancer cells in colonized tissue express DKKs to suppress NK cell activity (37, 40). Finally, NK cells undergo reprogramming to express inhibitory rather than activating receptors as metastatic cancer cells proliferate into macrometastases, and the reprogrammed NK cells can promote tumor growth (14).