Historical Evolution and CRISPR-Mediated Gene Editing Applications in NK Cell Therapy

Natural Killer (NK) cell therapy has emerged as a transformative approach in cancer immunotherapy, driven by decades of research since their discovery in the 1970s. NK cells possess a unique ability to target tumor cells through antigen-independent recognition, which has been expanded with the discovery of antigen-specific memory and licensing mechanisms. This review explores the evolution of NK cell biology, highlighting key findings such as the enhanced response of NK cells upon re-exposure to cytomegalovirus (CMV), defying conventional immune paradigms. Recent advancements in gene editing, particularly with CRISPR technology, have led to the development of "armored" NK cells. For example, knock-in strategies have enabled the insertion of chimeric antigen receptors (CAR), enhancing tumor specificity, while knock-out approaches have improved NK cell activation by removing inhibitory molecules like PD-1 and NKG2A. Early clinical trials demonstrate improved tumor-targeting efficacy and reduced resistance. However, challenges remain, including high R&D costs, limited clinical data, and technical uncertainties such as off-target effects. In China, NK cell therapy is in its nascent stages, with increasing interest but limited clinical applications due to regulatory and funding barriers. This review provides a comprehensive analysis of NK cell evolution, CRISPR-based advancements, and future directions for overcoming current limitations and optimizing therapeutic outcomes.