Natural killer cell epigenetic reprogramming in tumors and potential for cancer immunotherapy

Natural killer (NK) cells are critical members of the innate lymphoid cell population and have a pivotal role in cancer eradication. NK cell maturation, development and function are tightly regulated by epigenetic modifications, which can also be recruited for cancer propagation and immune escape. NK cells have the potential to be activated against tumors through several epigenetic regulators. Given that epigenetic changes are inducible and reversible, focusing on aberrant epigenetic regulations recruited by tumor cells provides a tremendous opportunity for cancer treatment. This review presents a comprehensive picture of NK cell normal epigenetic regulation and cancer-driven epigenetic modifications. From our perspective, a better understanding of epigenetic regulators that can edit and revise NK cells' activity is a promising avenue for NK cell-based therapy in cancer management.Natural killer (NK) cells are one of the critical cell types in our immune system, fighting against cancers, especially in the first stages of cancer formation. NK cells are produced in the bone marrow and develop to mature cells in the blood. NK cell development is tightly regulated in our body by different mechanisms, including genetic and epigenetic factors. Unlike genetic determinants, epigenetic factors are inducible and changeable via multiple triggers; for example, NK cell activity is enhanced after exercise. Cancers have an ‘intelligent’ function: they try to counteract the immune system and make it functionally impaired. So cancer cells produce different substances and use diverse mechanisms to suppress NK cell activity. In other words, they use epigenetic modifications to create inactive NK cells. Fortunately, as the epigenetic changes are reversible, it is possible to reverse epigenetic alterations and activate NK cells against cancers. There are some studies indicating the successful use of epigenetic modifiers in activating NK cells in labs. Furthermore, some studies have focused on the use of epigenetic modifiers of NK cell behavior in different human cancers. The more we know about the epigenetic modifications in normal NK cells, the higher possibility we have to create an anticancer treatment based on them.