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Updated: Dec 18, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Engineering of chimeric natural killer cell receptors to develop precision adoptive immunotherapies for cancer
J Obajdin1, D M Davies1, J Maher1,2,3,4
1School of Cancer and Pharmaceutical Sciences, CAR Mechanics Laboratory, Guy's Cancer Centre, King's College London, London, UK.
Abstract:
Natural killer (NK) cells are innate immune effectors which play a crucial role in recognizing and eliminating virally infected and cancerous cells. They effectively distinguish between healthy and distressed self through the integration of signals delivered by germline-encoded activating and inhibitory cell surface receptors. The frequent up-regulation of stress markers on genetically unstable cancer cells has prompted the development of novel immunotherapies that exploit such innate receptors. One prominent example entails the development of chimeric antigen receptors (CAR) that detect cell surface ligands bound by NK receptors, coupling this engagement to the delivery of tailored immune activating signals. Here, we review strategies to engineer CARs in which specificity is conferred by natural killer group 2D (NKG2D) or other NK receptor types. Multiple preclinical studies have demonstrated the remarkable ability of chimeric NK receptor-targeted T cells and NK cells to effectively and specifically eliminate cancer cells and to reject established tumour burdens. Importantly, such systems act not only acutely but, in some cases, they also incite immunological memory. Moreover, CARs targeted with the NKG2D ligand binding domain have also been shown to disrupt the tumour microenvironment, through the targeting of suppressive T regulatory cells, myeloid-derived suppressor cells and tumour vasculature. Collectively, these findings have led to the initiation of early-phase clinical trials evaluating both autologous and allogeneic NKG2D-targeted CAR T cells in the haematological and solid tumour settings.
Insights
Chimeric antigen receptors (CARs) engineered with natural killer (NK) receptors, like NKG2D, show promise in cancer immunotherapy. These CAR NK cells and T cells effectively target and eliminate tumors, potentially inciting long-term immune memory.
Area of Science:
- Immunology
- Cancer Biology
- Cell Therapy
Background:
- Natural killer (NK) cells are crucial innate immune cells that eliminate virally infected and cancerous cells by integrating signals from activating and inhibitory receptors.
- Cancer cells often up-regulate stress markers, making them targets for immunotherapies that leverage innate immune recognition.
- Chimeric antigen receptors (CARs) are engineered to redirect immune cells, like NK cells, to target cancer cells by binding specific ligands.
Purpose of the Study:
- To review strategies for engineering CARs utilizing NK receptors, such as NKG2D, for cancer immunotherapy.
- To highlight the preclinical efficacy and potential of CAR NK and T cells in eliminating tumors and inducing immune memory.
- To discuss the broader impact of NKG2D-targeted CARs on the tumor microenvironment and their progression into clinical trials.
Main Methods:
- Review of preclinical studies on CARs engineered with NK receptor specificities (e.g., NKG2D).
- Analysis of data demonstrating the efficacy of CAR NK and T cells against various cancer types.
- Examination of studies investigating the effects of CARs on the tumor microenvironment and immune memory.
Main Results:
- Preclinical studies show CAR NK and T cells effectively eliminate cancer cells and reduce tumor burden.
- Engineered CARs can elicit both acute anti-tumor responses and long-term immunological memory.
- NKG2D-targeted CARs can disrupt the tumor microenvironment by targeting suppressive cells and vasculature.
Conclusions:
- CARs incorporating NK receptors, particularly NKG2D, represent a promising strategy for cancer immunotherapy.
- CAR NK and T cells demonstrate significant preclinical efficacy and potential for inducing durable anti-tumor immunity.
- Early-phase clinical trials are underway to evaluate the safety and efficacy of NKG2D-targeted CAR T cells for hematological and solid tumors.
