文章：

工程化先天免疫：CAR-NK与CAR-巨噬细胞疗法在实体瘤中的最新进展与未来方向

Engineering Innate Immunity: Recent Advances and Future Directions for CAR-NK and CAR–Macrophage Therapies in Solid Tumors

原文发布日期：19 July 2025

DOI: 10.3390/cancers17142397

类型: Article

开放获取: 是

英文摘要：

Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered natural killer (CAR-NK) cells and chimeric antigen receptor–macrophages (CAR-MΦ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-MΦ therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcRγ), novel effector constructs (e.g., NKG7-overexpressing CARs, TME-responsive CARs), and scalable induced pluripotent stem cell (iPSC)-derived platforms. Preclinical data support enhanced antitumor activity through mechanisms such as major histocompatibility complex (MHC)-unrestricted cytotoxicity, phagocytosis, trogocytosis, cytokine secretion, and cross-talk with adaptive immunity. Early-phase clinical studies (e.g., CT-0508) demonstrate feasibility and TME remodeling with CAR-MΦ. However, persistent challenges remain, including transient in vivo survival, manufacturing complexity, and risks of off-target inflammation. Emerging combinatorial strategies, such as dual-effector regimens (CAR-NK+CAR-MΦ), cytokine-modulated cross-support, and bispecific or logic-gated CARs, may overcome these barriers and provide more durable, tumor-selective responses. Taken together, CAR-NK and CAR-MΦ platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain.

摘要翻译： 

过继性细胞疗法已彻底改变了血液系统恶性肿瘤的治疗格局。然而，其在实体瘤中的应用仍受限于抗原异质性、免疫抑制性肿瘤微环境（TME）以及传统CAR-T细胞持久性不足等问题。为此，天然免疫细胞平台，特别是嵌合抗原受体工程化自然杀伤细胞（CAR-NK）和嵌合抗原受体巨噬细胞（CAR-MΦ），已成为具有前景的替代方案。本综述总结了CAR-NK和CAR-MΦ疗法在实体瘤中的设计与应用最新进展，重点阐述了关键创新技术，包括谱系特异性细胞内信号域（如DAP12、2B4、FcRγ）的应用、新型效应器构建体（如过表达NKG7的CAR、TME响应型CAR）以及可扩展的诱导多能干细胞（iPSC）衍生平台。临床前数据表明，这些疗法通过主要组织相容性复合体（MHC）非限制性细胞毒性、吞噬作用、胞啃作用、细胞因子分泌以及与适应性免疫的交互作用等机制，增强了抗肿瘤活性。早期临床研究（如CT-0508）证实了CAR-MΦ疗法的可行性及其对TME的重塑能力。然而，仍存在持续性挑战，包括体内存活时间短暂、生产工艺复杂以及脱靶炎症风险。新兴的联合策略，如双效应细胞疗法（CAR-NK+CAR-MΦ）、细胞因子调节的交叉支持以及双特异性或逻辑门控CAR，可能突破这些障碍，提供更持久、肿瘤选择性的应答。综上所述，CAR-NK和CAR-MΦ平台有望将工程化细胞疗法的应用范围扩展至实体瘤领域。

原文链接：

Engineering Innate Immunity: Recent Advances and Future Directions for CAR-NK and CAR–Macrophage Therapies in Solid Tumors