肿瘤细胞治疗研究
英文原题：Harnessing CAR-NK cells against multiple myeloma: current landscape and future directions.
CAR-NK 疗法正从一种有前景的概念演变为针对 MM 的现实治疗平台。
背景：多发性骨髓瘤（MM）仍是一种侵袭性强且基本无法治愈的浆细胞恶性肿瘤，尽管治疗已有进展，复发仍很常见。CAR-T细胞已改变这一领域，但其临床应用受到毒性、生产复杂和可及性有限的制约。这些局限推动了人们对CAR工程化NK 细胞（CAR-NK）的兴趣，后者可能成为更安全、可规模化且可现货使用的免疫治疗平台。 目的：本综述超越对MM CAR-NK研究的描述性总结，提供一个整合框架，将抗原靶向、合成工程、肿瘤微环境适应、生物标志物指导的应答监测及转化生产障碍联系起来。综述不仅总结已有成果，也指出限制临床应用的因素及该领域最可能的发展方向。 方法：我们全面分析MM CAR-NK细胞疗法的临床前和临床研究，重点关注靶点选择、增强持久性的策略、免疫逃逸、生物标志物开发、联合治疗方法及符合GMP要求的生产平台。 结果：相较CAR-T，CAR-NK具有若干优势，包括细胞因子释放综合征、神经毒性和移植物抗宿主病风险较低。除总结当前研究的BCMA、CD138、SLAMF7和GPRC5D等靶点外，本综述还指出推动下一代CAR-NK开发的主要设计原则：细胞因子装甲化、基因组编辑、双靶点策略和纳米技术辅助递送。重要的是，我们还综合了新兴转化重点，包括用于患者分层的预测性生物标志物、治疗应答的连续监测，以及可能决定临床可行性的可规模化封闭系统生产方法。 结论：CAR-NK疗法正从有前景的概念发展为MM的现实治疗平台。本综述整合工程创新、生物标志物驱动的精准医疗和生产可扩展性，提出前瞻性转化路线图，并界定推动CAR-NK用于难治性MM、实现持久且具有临床意义影响所需的关键步骤。
BACKGROUND: Multiple myeloma (MM) remains an aggressive and largely incurable plasma cell malignancy, with relapse common despite therapeutic advances. Although CAR-T cells have transformed the field, their clinical use is constrained by toxicity, complex manufacturing, and limited accessibility. These limitations have accelerated interest in CAR-engineered natural killer (CAR-NK) cells as a safer, more scalable, and potentially off-the-shelf immunotherapeutic platform. OBJECTIVE: This review goes beyond a descriptive summary of CAR-NK research in MM by providing an integrated framework that connects antigen targeting, synthetic engineering, tumor microenvironment adaptation, biomarker-guided response monitoring, and translational manufacturing barriers. In doing so, it highlights not only what has been achieved, but also what currently limits clinical implementation and where the field is most likely to advance next. METHODS: We performed a comprehensive literature analysis of preclinical and clinical studies on CAR-NK cell therapy in MM, focusing on target selection, persistence-enhancing strategies, immune evasion, biomarker development, combination approaches, and GMP-compatible manufacturing platforms. RESULTS: CAR-NK cells offer several advantages over CAR-T therapy, including lower risks of cytokine release syndrome, neurotoxicity, and graft-versus-host disease. Beyond summarizing currently explored targets such as BCMA, CD138, SLAMF7, and GPRC5D, this review identifies the main design principles driving next-generation CAR-NK development: cytokine armoring, genome editing, dual-targeting strategies, and nanotechnology-enabled delivery. Importantly, we also synthesize emerging translational priorities, including predictive biomarkers for patient stratification, serial monitoring of treatment response, and scalable closed-system manufacturing approaches that may determine clinical feasibility. CONCLUSION: CAR-NK therapy is evolving from a promising concept into a realistic therapeutic platform for MM. This review contributes a forward-looking translational roadmap by integrating engineering innovation, biomarker-based precision medicine, and manufacturing scalability, thereby defining the key steps needed to move CAR-NK cells toward durable and clinically meaningful impact in refractory MM.
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