Wei Xiyao, Su Chen, Liu Yueyang, Wei Ningbo, Xiang Kexin, Qian Qijun, Xu Zenghui
Shanghai Cell Therapy Group Co., Ltd., Shanghai 201805, P.R. China.
Mol Med Rep. 2025 Aug;32(2). doi: 10.3892/mmr.2025.13587. Epub 2025 Jun 6.
Natural killer (NK) cell‑based immunotherapy has emerged as a transformative approach for cancer treatment However, its widespread clinical application faces several challenges, such as donor variability, limited scalability and functional heterogeneity of primary NK cells. Additionally, issues including persistence, resistance to tumor microenvironment and safety concerns related to genomic instability further hinder its clinical application. Induced pluripotent stem cell (iPSC)‑derived NK cells offer a promising solution. They provide high homogeneity and quality control, genetic engineering flexibility and inexhaustible cell source. This present review highlighted the unique advantages of iPSC‑ NK cells, including clonal uniformity, enhanced cytotoxicity and suitability for large‑scale production, positioning them as an ideal 'off‑the‑shelf' therapeutic platform. It discussed the biological properties of iPSC‑derived NK cells, advances in differentiation protocols and strategies to augment their anti‑tumor efficacy through genetic engineering, such as chimeric antigen receptor integration and cytokine optimization. Despite these advantages, several challenges remain, including the need to optimize differentiation efficiency, ensure the safety of gene editing (such as off‑target effects) and improve the migration and infiltration abilities. With technological advances and clinical validation, this present review aimed to guide future research toward overcoming these barriers to clinical implementation. Ultimately, it is expected that iPSC‑NK will become a core means of next‑generation immunotherapy, promoting the combination of personalized and inclusive cancer treatment.
基于自然杀伤（NK）细胞的免疫疗法已成为一种变革性的癌症治疗方法。然而，其广泛的临床应用面临着诸多挑战，如供体变异性、原代NK细胞的可扩展性有限和功能异质性。此外，包括持久性、对肿瘤微环境的抗性以及与基因组不稳定性相关的安全性问题等，进一步阻碍了其临床应用。诱导多能干细胞（iPSC）衍生的NK细胞提供了一个有前景的解决方案。它们具有高度同质性和质量可控性、基因工程灵活性以及无穷尽的细胞来源。本综述强调了iPSC-NK细胞的独特优势，包括克隆一致性、增强的细胞毒性和适合大规模生产，使其成为理想的“现成可用”治疗平台。它讨论了iPSC衍生的NK细胞的生物学特性、分化方案的进展以及通过基因工程增强其抗肿瘤功效的策略，如嵌合抗原受体整合和细胞因子优化。尽管有这些优势，但仍存在一些挑战，包括需要优化分化效率、确保基因编辑的安全性（如脱靶效应）以及提高迁移和浸润能力。随着技术进步和临床验证，本综述旨在指导未来研究克服这些临床应用障碍。最终，预计iPSC-NK将成为下一代免疫疗法的核心手段，推动个性化和包容性癌症治疗的结合。
