Balkhi Sahar, Zuccolotto Gaia, Di Spirito Anna, Rosato Antonio, Mortara Lorenzo
Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy.
Front Immunol. 2025 Apr 7;16:1574742. doi: 10.3389/fimmu.2025.1574742. eCollection 2025.
Over the past few years, cellular immunotherapy has emerged as a promising treatment for certain hematologic cancers, with various CAR-T therapies now widely used in clinical settings. However, challenges related to the production of autologous cell products and the management of CAR-T cell toxicity highlight the need for new cell therapy options that are universal, safe, and effective. Natural killer (NK) cells, which are part of the innate immune system, offer unique advantages, including the potential for off-the-shelf therapy. A recent first-in-human trial of CD19-CAR-NK infusion in patients with relapsed/refractory lymphoid malignancies demonstrated safety and promising clinical activity. Building on these positive clinical outcomes, current research focuses on enhancing CAR-NK cell potency by increasing their persistence and addressing functional exhaustion. There is also growing interest in applying the successes seen in hematologic malignancies to solid tumors. This review discusses current trends and emerging concepts in the engineering of next-generation CAR- NK therapies. It will cover the process of constructing CAR-NK cells, potential targets for their manufacturing, and their role in various solid tumors. Additionally, it will examine the mechanisms of action and the research status of CAR-NK therapies in the treatment of solid tumors, along with their advantages, limitations, and future challenges. The insights provided may guide future investigations aimed at optimizing CAR-NK therapy for a broader range of malignancies.
在过去几年中，细胞免疫疗法已成为某些血液系统癌症的一种有前景的治疗方法，目前各种嵌合抗原受体T细胞（CAR-T）疗法在临床环境中广泛使用。然而，与自体细胞产品生产以及CAR-T细胞毒性管理相关的挑战凸显了对通用、安全且有效的新型细胞疗法的需求。作为先天免疫系统一部分的自然杀伤（NK）细胞具有独特优势，包括现成可用疗法的潜力。最近一项针对复发/难治性淋巴系统恶性肿瘤患者进行的CD19-CAR-NK输注的首次人体试验证明了其安全性和有前景的临床活性。基于这些积极的临床结果，当前研究集中于通过提高CAR-NK细胞的持久性和解决功能耗竭问题来增强其效力。将血液系统恶性肿瘤中取得的成功应用于实体瘤的兴趣也在不断增加。本综述讨论了下一代CAR-NK疗法工程中的当前趋势和新兴概念。它将涵盖构建CAR-NK细胞的过程、其制造的潜在靶点以及它们在各种实体瘤中的作用。此外，它将研究CAR-NK疗法在实体瘤治疗中的作用机制和研究现状，以及它们的优势、局限性和未来挑战。所提供的见解可能会指导未来旨在优化CAR-NK疗法以治疗更广泛恶性肿瘤的研究。
