Natural killer cells as a promising therapeutic target for cancer immunotherapy.

Natural killer (NK) cells are innate lymphoid cells that provide early protection against cancer development via their selectivity to kill abnormal cells undergoing cellular transformation without the need for prior stimulation. Given the correlation between NK cell dysfunction and cancer prognosis, restoration of endogenous NK cells in the tumor microenvironment or adoptive transfer of NK cells with improved function holds great promise in cancer treatment. Furthermore, MHC-unrestricted tumor lysis by NK cells complements the MHC-restricted killing of tumor cells by cytotoxic T cells, thus positioning NK cells as an alternative or complementary therapeutic target for cancers that are refractory to T cell-based therapy. Although previous therapeutic strategies have focused on the manipulation of NK cell inhibitory receptors, recent advances in our understanding of NK cell activation have provided additional promising strategies to enhance NK cell reactivity against cancer. These approaches include targeting immunosuppressive mechanisms in the tumor microenvironment, such as immune checkpoint receptors, and further enhancing NK cell activation via modulation of intracellular checkpoint molecules or incorporation of tumor-directed chimeric antigen receptors. Thus, an in-depth understanding of NK cell activation will facilitate the optimal design of therapeutic strategies against refractory cancers, possibly in rational and synergistic combination with other therapies.