Engineering Natural Killer Cells for Cancer Therapy: Strategies to Enhance Persistence, Metabolic Fitness, and Cytotoxicity

Abstract

Natural killer (NK) cells are important components of the innate immune system that has the ability to recognize and eliminate virally infected and malignant cells without prior antigen detection. Their potent cytotoxic activity and favorable safety have made them promising cells for cancer immunotherapy. However, the clinical efficacy of NK cell-based therapies is often limited by poor persistence, metabolic exhaustion, and suppression within the tumor microenvironment. Recent advances in genetic engineering have focused on overcoming these barriers by increasing NK cell survival, fitness, and antitumor function. This literature review looks at several emerging methods designed to improve NK cell performance, including cytokine engineering with interleukin-15 (IL-15), chimeric antigen receptor (CAR) modification, and targeted gene editing approaches such as CISH and FLI1 deletion. Evidence from recent preclinical studies have demonstrated that IL-15 engineering increases metabolic fitness and persistence, CAR-NK technology improves tumor-specific targeting while maintaining innate cytotoxicity, and gene-editing approaches increase NK cell responsiveness and memory properties. Among these strategies, the combination of IL-15 engineering and CISH deletion appears the most promising because it simultaneously provides external cytokine support and removes intrinsic inhibitory signaling pathways. Together, these advances show the potential of engineered NK cells to overcome current therapeutic limitations and improve the effectiveness of cancer immunotherapy. Future studies evaluating the safety, durability, and clinical applicability of these approaches will be necessary for translation of these findings into widespread therapeutic use.