肿瘤细胞治疗研究
英文原题：Engineering Innate Immunity: Recent Advances and Future Directions for CAR-NK and CAR-Macrophage Therapies in Solid Tumors.
过继性细胞疗法已改变了血液系统恶性肿瘤的治疗格局。
过继性细胞疗法已改变血液系统恶性肿瘤的治疗格局。然而，向实体瘤的转化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 细胞持久性差。为此，固有免疫细胞平台，尤其是嵌合抗原受体工程化自然杀伤（CAR-NK）细胞和嵌合抗原受体巨噬细胞（CAR-M），已成为有前景的替代方案。本综述总结了 CAR-NK 和 CAR-M 疗法在实体瘤中设计与应用的最新进展。我们重点介绍关键创新，包括谱系特异性胞内信号结构域（如 DAP12、2B4、FcR）的使用、新型效应构建体（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。临床前数据支持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、胞吐作用、细胞因子分泌以及与适应性免疫的交叉对话等机制增强抗肿瘤活性。早期临床研究（如 CT-0508）证明了 CAR-M 的可行性及 TME 重塑作用。然而，持续存在的挑战仍然包括体内存活短暂、生产复杂性以及脱靶炎症风险。新兴的联合策略，如双效应方案（CAR-NK + CAR-M）、细胞因子调节的交叉支持以及双特异性或逻辑门控 CAR，可能克服这些障碍并提供更持久、肿瘤选择性的应答。综上所述，CAR-NK 和 CAR-M 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。
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-M ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-M therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcR ), 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-M . 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-M ), 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-M platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain.
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