The cancer–natural killer cell immunity cycle


Immunotherapy with checkpoint blockade induces rapid and durable immune control of cancer in some patients and has driven a monumental shift in cancer treatment. Neoantigen-specific CD8+ T cells are at the forefront of current immunotherapy strategies, and the majority of drug discovery and clinical trials revolve around further harnessing these immune effectors. Yet the immune system contains a diverse range of antitumour effector cells, and these must function in a coordinated and synergistic manner to overcome the immune-evasion mechanisms used by tumours and achieve complete control with tumour eradication. A key antitumour effector is the natural killer (NK) cells, cytotoxic innate lymphocytes present at high frequency in the circulatory system and identified by their exquisite ability to spontaneously detect and lyse transformed or stressed cells. Emerging data show a role for intratumoural NK cells in driving immunotherapy response and, accordingly, there have been renewed efforts to further elucidate and target the pathways controlling NK cell antitumour function. In this Review, we discuss recent clinical evidence that NK cells are a key immune constituent in the protective antitumour immune response and highlight the major stages of the cancer–NK cell immunity cycle. We also perform a new analysis of publicly available transcriptomic data to provide an overview of the prognostic value of NK cell gene expression in 25 tumour types. Furthermore, we discuss how the role of NK cells evolves with tumour progression, presenting new opportunities to target NK cell function to enhance cancer immunotherapy response rates across a more diverse range of cancers.

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Fig. 1: The tumour cell:natural killer cell interactome.
Fig. 2: Prognostic value of natural killer cells in cancer.
Fig. 3: The cancer–natural killer cell immunity cycle.
Fig. 4: Natural killer cell-mediated tumour immunoediting and escape.


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N.D.H., J.C. and J.R. all researched the data for the article and provided substantial contributions to discussions of the content. N.D.H and J.C. contributed equally to writing the article. N.D.H, J.C. and J.R. all reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Nicholas D. Huntington or Joseph Cursons.

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Competing interests

N.D.H. and J.R. are founders and shareholders of oNKo-Innate Pty Ltd, and J.R. and J.C. are employees of oNKo-Innate Pty Ltd.

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Nature Reviews Cancer thanks A. Cerwenka, L. Lanier and K.-J. Malmberg for their contribution to the peer review of this work.

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Supplementary information


Major histocompatibility complex class I

(MHC-I). Cell surface molecules widely expressed across most cells and tissues that play a role in presenting small portions of processed intracellular or internal proteins for immunosurveillance by CD8+ T cells. Classical MHC-I genes include human leukocyte antigen A (HLA-A), HLA-B and HLA-C. Non-classical MHC-I genes include HLA-E, HLA-F and HLA-G as well as the UL16 binding protein (ULBP) gene family and can interact with natural killer cells.

Cytotoxic granules

Intracellular or internal structures that package proteins (granzymes and perforin) and are secreted to kill another cell. These are important for the function of immune effector cells, such as natural killer cells and subsets of T cells.

Hazard ratio

(HR). A statistical metric quantifying the extent to which a variable (for example, the transcript abundance of a given gene) is associated with an increased (HR >1, log(HR) >0) or decreased (HR <1, log(HR) <0) hazard for the patient, relative to a baseline hazard.

Pearson’s correlation coefficient

(rP). A summary statistic that provides a measure of linear association between two variables; rP varies from –1 (perfect negative linear association) through 0 (no association) to 1 (perfect positive linear association).


A term used to describe donor and recipient tissue samples (for example, a bone marrow stem cell transplant) where the human leukocyte antigen (HLA) genetic variants (‘haplotype’) are ‘half-matched’ (for example, from a parent or, in some cases, a sibling), reducing the risk of rejection or other immune side effects.

Human leukocyte antigen

(HLA). Clusters of genes encoding various components or subsets of the major histocompatibility complex (MHC), which are involved in immune cell recognition. These genetic regions tend to vary considerably between individuals (that is, there are numerous ‘polymorphisms’).

MHC class II

(MHC-II). Cell surface molecules with expression generally restricted to ‘antigen presenting cells’ (such as dendritic cells and macrophages). These cells take up extracellular particles through phagocytosis and can process and present antigen through MHC-II for activation of CD4+ helper T cell populations.


A class of enzyme that catalyses the conversion of nucleotides to nucleosides (for example, adenosine monophosphate (AMP) to adenosine). These enzymes are often expressed on the cell surface, where they modulate purinergic signalling.

Immunogenic cell death

Cellular death programmes that elicit immune activation. Examples relevant to cancer include necroptosis (induced by FAS–tumour necrosis factor (TNF) signalling) and endoplasmic reticulum stress-induced death (driven by drug treatment) leading to secretion of immunostimulatory damage-associated molecular patterns.

Cytokine release syndrome

(CRS). An adverse event where systemic cytokine signalling triggers further immune activation and cytokine release through positive feedback, often leading to organ failure without therapeutic intervention.

Graft versus host disease

(GvHD). A common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as foreign and mount an immunological attack.

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Huntington, N.D., Cursons, J. & Rautela, J. The cancer–natural killer cell immunity cycle. Nat Rev Cancer 20, 437–454 (2020).

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