Numerous reviews in the field of NK cell biology dictate the pivotal role that NK cells play in tumor
rejection. Although these cell types were originally described based on their cytotoxic ability, we now know that
NK cells are not naturally born to kill. Both cellular interactions and the local environment in which the NK cell
resides in may influence its cytotoxic functions. Just as organ specific NK cells have distinct phenotypic and
functional differences, the tumor is a unique microenvironment in itself. The NK cells originally recruited to the
tumor site are able to stimulate immune responses and aid in tumor destruction but eventually become
persuaded otherwise by mechanisms of immunosuppression. Here, we review potential mechanisms and
players involved in NK cell immunosuppression. In particular the effects of another innate immune player,
macrophages, will be addressed in augmenting immunosuppression of NK cells within tumors. Tumorassociated
macrophages (TAMs) are the main regulatory population of myeloid cells in the tumor and are
characterized by their ability to promote tumor cell proliferation and metastasis. In addition, they
express/release immunoregulatory factors which have been shown to directly inhibit NK cell function.
Understanding how these two cell types interact in the distinct tumor microenvironment will allow us to consider
therapies that target TAMs to promote enhanced NK cell activity.