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Review
. 2024 Mar 15;13(3):230-242.
doi: 10.1093/stcltm/szad087.

Genetic Manipulation Approaches to Enhance the Clinical Application of NK Cell-Based Immunotherapy

Andreia Maia  1   2   3 , Mubin Tarannum  3 , Rizwan Romee  3
Affiliations
Review

Genetic Manipulation Approaches to Enhance the Clinical Application of NK Cell-Based Immunotherapy

Andreia Maia et al. Stem Cells Transl Med. .

Abstract

Natural killer (NK) cells are a subset of cytotoxic lymphocytes within the innate immune system. While they are naturally cytotoxic, genetic modifications can enhance their tumor-targeting capability, cytotoxicity, persistence, tumor infiltration, and prevent exhaustion. These improvements hold the potential to make NK-cell-based immunotherapies more effective in clinical applications. Currently, several viral and non-viral technologies are used to genetically modify NK cells. For nucleic acid delivery, non-viral methods such as electroporation, lipid nanoparticles, lipofection, and DNA transposons have gained popularity in recent years. On the other hand, viral methods including lentivirus, gamma retrovirus, and adeno-associated virus, remain widely used for gene delivery. Furthermore, gene editing techniques such as clustered regularly interspaced short-palindromic repeats-based, zinc finger nucleases, and transcription activator-like effector nucleases are the pivotal methodologies in this field. This review aims to provide a comprehensive overview of chimeric antigen receptor (CAR) arming strategies and discuss key gene editing techniques. These approaches collectively aim to enhance NK cell/NK cell CAR-based immunotherapies for clinical translation.

Keywords: CAR-NK cells; CRISPR; cytokine-induced memory-like NK cells; gene delivery; gene editing; immunotherapy; natural killer cells.

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Conflict of interest statement

The author indicated no financial relationships.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Major gene delivery methods used for genetic manipulation of NK cells. Cells can be genetically modified transiently when DNA is not integrated into the genome or in a stable manner when DNA is integrated into the genome. Currently, there are different methods for gene delivery which can be viral dependent using gamma retrovirus, lentivirus, adeno-associated virus, or non-viral-dependent methodologies such as lipofection, electroporation, DNA transposons, and lipid nanoparticles.
Figure 2.
Figure 2.
Gene editing strategies used for NK-cell editing. The precise genetic alteration of NK cells is allowed by the development of key gene editing methodologies such as zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology, and its derivatives like base editing and prime sediting methodologies.
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