Melanoma is the most aggressive and deadliest form of
skin cancer, and its prognosis is very poor. Although the early detection is responsive to many treatments, metastatic
melanoma is refractory to most of them. In the United States, skin
melanoma is the fifth most common type of
cancer in men and the sixth in women. Current treatment modalities, depending on the
cancer stage, consist primarily of surgical excision,
chemotherapy, adjuvant therapy, targeted
therapies, and
immunotherapy. Despite the wide range of therapeutic options and the steadily increasing response rates, a large subset of the treated patients relapse and develop resistance to further treatments. One novel approach in preclinical and clinical trials in
immunotherapy is the adaptation of natural killer (NK) cells against resistant
cancer cells. NK cells can kill a variety of
cancer cell types, as well as the cancer stem cells, while leaving normal cells intact. In skin
melanoma, as in most
cancers, NK cells in the tumor microenvironment (TME) are functionally impaired. Several factors underlie the defective cause of NK cells, one of which is the dysregulation of the activating
receptor NKG2D. This is the dominant receptor in regulating the cytotoxic activity,
cytokine production, and regulation of other receptors expressed on NK cells and other lymphocytes. The defective NK cells in
cancer models were associated with
tumor growth and
metastasis. In this review, we discuss the role of NK cells and their phenotypic variants in skin
melanoma. Using bioinformatics, we have further analyzed the expression of NKG2D, confirming its low transcript levels in patients with skin
melanoma. Furthermore, we show that the CD133 subset of cancer stem cells expresses low levels of NKG2D. Based on these findings we discuss the potential therapeutic approaches that can be exploited to upregulate NKG2D in patients' NK cells and restore their anti-
melanoma effects, resulting in
tumor regression and prolonged survival.