Natural killer (NK) cells were first described in the 1970s for their ability to destroy tumor cells without prior sensitization to tumor antigens [1]. They are effector cells of the innate immune system, accounting for 5–10 % of peripheral blood lymphocytes, and belong to the family of innate lymphoid cells (ILCs) [2]. Based on cytokine production and transcription factor expression, three groups of ILCs have been identified: ILC1s, which include interferon-γ (IFN-γ)-producing NK cells, ILC2s that produce cytokines that stimulate classical TH2 (T-helper 2) cells and mediate responses against large extracellular pathogens, and ILC3s that produce cytokines that simulate TH17 (T-helper 17) cells [3,4]. NK cells are further classified into two subsets, identified by their surface expression of CD56 and CD16. CD56bright and CD16low/- cells function to modulate immune responses and produce cytokines, whereas CD56dim and CD16+ cells are cytotoxic. For the purposes of this review, the focus of this review will be primarily on the cytoxic subset of NK cells [5].

NK cells play an important role in immune surveillance as cytotoxic lymphocytes, recognizing and eliminating malignant or infected cells. A key feature of NK cells is their inhibition by receptors that bind major histocompatibility complex class I (MHC I) molecules via inhibitory killer Ig-like receptors (KIRs); this interaction depends on education by self MHC I. Thus, when cells lose MHC I expression, as is the case in many solid tumor malignancies, this KIR/MHC mismatch promotes cytolytic activity of NK [6]. This further becomes important in allogeneic hematopoietic stem cell transplant and adoptive cell therapy, when there is MHC mismatch, allowing enhanced NK cell killing of cancer cells. Additionally, tumor cells that lose MHC I expression can evade CD8+ T cell responses, particularly in the context of checkpoint blockade immunotherapy, which makes NK cells important for complementing T cell-based therapies [6].

In spite of expression of inhibitor KIRs, NK cells are still capable of killing MHC I-expressing tumor cells. This occurs when tumor cells display high levels of NK cell-activating ligands, which override the inhibitory signals mediated by MHC I recognition [6]. This dual functionality underscores NK cells’ potential for use in combination cancer therapies, particularly in tumors resistant to CD8+ T cell-mediated immune responses. Additionally, as innate immune cells, NK cells do not require antigen specificity for activation, and can rapidly recognize and destroy abnormal cells without the need for prior antigen sensitization or MHC restriction [7]. Thus, NK cells may actually be preferential for treating cancers with low antigen load.

One of the concerns for adoptive cell therapy, especially with the non-specific activity of NK cells is the risk of graft-vs-host (GvHD) disease, in which donor NK cells target healthy cells to cause organ damage. However, as described in this review, no studies to date have demonstrated evidence of GvHD disease in adoptive NK cell therapy.

In general, adoptive T cell therapy requires autologous isolation of lymphocytes and ex vivo transduction and expansion. By contrast, adoptive NK cell therapy does not need to be autologous, thus allowing the potential for large-scale production of a universal donor product, reducing costs and time to infusion for patients. Indeed, NK cells can be sourced from healthy donors, overcoming limitations seen with T-cell therapies and reducing costs for large-scale production [8]. Various NK cell sources are currently utilized in adoptive cancer immunotherapy, including autologous, allogeneic, umbilical cord blood-derived, cell lines, and induced pluripotent stem cells with newer approaches now to generate genetically engineered NK cells for enhanced targeting and activity [9].

Overall, the therapeutic use of NK cells may complement and enhance current immunotherapies by bridging the gap where T cell responses alone are insufficient. These unique characteristics make NK cells an attractive option for the treatment of various types of cancers and there is growing interest in exploring the use of NK cell therapies for other indications, such as viral infections or autoimmune conditions. This review focuses on the current status and recent advances in NK cell-based immunotherapy in cancer, including autologous and allogeneic NK cells, genetically modified chimeric antigen receptor (CAR)-NK cells, and the clinical trials being conducted in this field.