Liao Yanling, Cairo Mitchell S
Pediatrics, New York Medical College, Valhalla, New York, USA.
Pediatrics, New York Medical College, Valhalla, New York, USA
J Immunother Cancer. 2025 May 21;13(5):e012139. doi: 10.1136/jitc-2025-012139.
Chimeric antigen receptor (CAR) therapies have revolutionized cancer treatment by enabling immune cells to target tumor cells with high specificity. While extensive research has focused on optimizing single-chain variable fragment (scFv) affinity in CAR-T cells, its impact on CAR-natural killer (NK) cell function remains less understood. A recent study by Rahnama , published in the , addresses this gap by investigating how fine-tuning scFv affinity influences CAR-NK efficacy against acute myeloid leukemia. The study demonstrates that lower-affinity 7G3-based CAR-NK cells exhibit superior antigen discrimination, prolonged persistence, and enhanced tumor control compared with their high-affinity counterparts. However, findings with 26292-based CAR-NK cells reveal a more complex, context-dependent relationship between scFv affinity and cytotoxic function. These results highlight the need for individualized optimization of CAR designs, considering factors such as epitope accessibility, ligand-binding kinetics, and cellular context. Future studies incorporating real-time kinetic analyses and tumor microenvironment modeling will be crucial for refining CAR-NK therapies. Striking the right balance between binding affinity, dwell time, and serial killing capacity could enhance CAR-NK therapeutic potential while minimizing toxicity risks.
嵌合抗原受体（CAR）疗法通过使免疫细胞能够高度特异性地靶向肿瘤细胞，彻底改变了癌症治疗方式。尽管大量研究集中在优化CAR-T细胞中单链可变片段（scFv）的亲和力上，但它对CAR-自然杀伤（NK）细胞功能的影响仍鲜为人知。拉赫纳马最近发表在《 》上的一项研究，通过研究微调scFv亲和力如何影响CAR-NK细胞对急性髓系白血病的疗效，填补了这一空白。该研究表明，与高亲和力的同类细胞相比，低亲和力的基于7G3的CAR-NK细胞表现出更好的抗原辨别能力、更长的持久性和更强的肿瘤控制能力。然而，基于26292的CAR-NK细胞的研究结果揭示了scFv亲和力与细胞毒性功能之间更为复杂的、依赖于环境的关系。这些结果凸显了在考虑表位可及性、配体结合动力学和细胞环境等因素的情况下，对CAR设计进行个性化优化的必要性。未来纳入实时动力学分析和肿瘤微环境建模的研究对于完善CAR-NK疗法至关重要。在结合亲和力、驻留时间和连续杀伤能力之间找到合适的平衡，可增强CAR-NK的治疗潜力，同时将毒性风险降至最低。
