NK cells and cancer: you can teach innate cells new tricks

Key Points Natural killer (NK) cells have a primordial role in tumour immunosurveillance. Given their potent antitumour activity, therapeutic manipulation of NK cells provides an attractive strategy for cancer treatment. A balance of inhibitory and stimulatory signals delivered by numerous receptors regulates NK cell functions (cytotoxicity, cytokine production and proliferation). NKG2D is the best characterized of these activating receptors and is directly involved in the recognition of tumours that express NKG2D ligands. NK cells detect and eliminate tumour cells that are deficient in major histocompatibility complex (MHC) class I molecules (missing self), have upregulated stress ligands that are recognized by activating NK cell receptors (induced self), or are coated with antibodies specific for tumour antigens, enabling recognition by NK cells expressing the CD16 Fc receptor, which triggers antibody-dependent cell-mediated cytotoxicity. Immunoediting of tumour cells by NK cells leads to tumour variants that can evade NK cell-mediated responses. Direct and indirect tumour escape mechanisms include secretion of immunosuppressive factors, shedding of ligands for the activating NK cell receptors and induction of ligands for activating NK cell receptors on healthy cells that can serve as decoys. Current checkpoint blockade agents used to activate T cells in cancer patients, such as antibodies against PD1, may also target NK cells. Checkpoint blockade targeting inhibitory receptors shared by NK cells and T cells are currently under clinical evaluation. In addition to engineered T cells, NK cells and their receptors represent an attractive alternative for the use of chimeric antigen receptors. Immunotherapeutic approaches such as the generation of bispecific linkers that engage activating NK cell receptors and tumour-specific antigens are also being developed to unleash the antitumour potential of NK cells. This Review discusses the role of natural killer (NK) cells in immunosurveillance of tumour cells, highlighting the new therapeutic approaches to NK cell targeting in the treatment of cancer and improvement of NK cell-mediated antitumour immune responses. Natural killer (NK) cells are the prototype innate lymphoid cells endowed with potent cytolytic function that provide host defence against microbial infection and tumours. Here, we review evidence for the role of NK cells in immune surveillance against cancer and highlight new therapeutic approaches for t