Natural Killer Cell Immunology and Cancer Therapeutics

Natural killer (NK) cells are innate lymphocytes that detect and eliminate transformed or infected cells without prior sensitisation. Their activity is regulated by a balance of activating and inhibitory receptors, enabling discrimination between healthy and abnormal cells. In cancer, NK cells contribute to immune surveillance through direct cytotoxicity, cytokine secretion and orchestration of adaptive responses. Therapeutic strategies harness these properties by expanding or engineering NK cells ex vivo, by deploying monoclonal antibodies that trigger antibody-dependent cellular cytotoxicity, and by designing synthetic constructs such as chimeric antigen receptors or multispecific engagers that enhance tumour targeting. Advances in donor selection, cytokine support and genetic modification have yielded allogeneic NK products with improved persistence and safety profiles. Understanding the tumour microenvironment, which can suppress NK-cell function through metabolic and immunosuppressive cues, is critical to optimise combination regimens and to overcome resistance in both haematological malignancies and solid tumours. The global significance of NK-cell-based therapies lies in their potential for off-the-shelf use, low incidence of severe toxicities and synergy with existing immunotherapeutic modalities.

Research from Nature Portfolio

Recent clinical investigation of cord blood-derived NK cells engineered to express an anti-CD19 chimeric antigen receptor alongside interleukin-15 has demonstrated a favourable safety profile, with no significant cytokine release syndrome or neurotoxicity. In patients with CD19-positive B cell malignancies, this approach achieved nearly 50 % overall response rates at both 30 and 100 days post-infusion. Persistence of the engineered cells correlated with durable remissions, and key predictors of outcome included the quality of the cord blood unit, notably cell composition and processing timelines.

In acute myeloid leukaemia models, a trifunctional engager molecule directed NKp46 and CD16a on NK cells towards CD123 on blast cells, eliciting potent cytotoxicity irrespective of inhibitory receptor expression. This engager induced selective NK-cell activation only in the presence of target cells, outperformed benchmark antibodies in preclinical models and achieved prolonged depletion of CD123-positive cells in nonhuman primates without overt toxicity. These findings support further clinical translation of NK-cell engagers for haematological cancers.

Natural Killer Cell Immunology and Cancer Therapeutics publication trend

The graph below shows the total number of articles in natural killer cell immunology and cancer therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Natural Killer (NK) cell: Innate lymphocyte that recognises and kills stressed or transformed cells without prior sensitisation.

Chimeric antigen receptor (CAR): Synthetic receptor grafted onto immune cells to direct antigen-specific tumour targeting.

Antibody-dependent cellular cytotoxicity (ADCC): Mechanism by which NK cells lyse antibody-coated target cells via Fc receptor engagement.

Tumour microenvironment: Complex milieu of cancer cells, stromal components and immune cells influencing tumour growth and therapy response.

References

1. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial. Nature Medicine (2024).
2. A pan-cancer single-cell panorama of human natural killer cells. Cell (2023).
3. Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123. Nature Biotechnology (2023).
4. NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. Cell (2018).