Sueangoen Natthaporn, Prasongtanakij Somsak
Research Laboratory section, Offices of Health Science Research, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Clin Exp Med. 2025 Aug 4;25(1):274. doi: 10.1007/s10238-025-01820-x.
Chimeric antigen receptor-based immunotherapy has transformed cancer treatment, especially for hematologic malignancies like acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Innovations in CAR design from first-generation constructs relying on CD3ζ signaling to next-generation CARs with co-stimulatory domains have enhanced T cell persistence and antitumor efficacy. Despite these successes, translating CAR-T therapy to solid tumors faces significant challenges, including antigen heterogeneity, immunosuppressive tumor microenvironments, and toxicities such as cytokine release syndrome and neurotoxicity. To overcome these hurdles, CAR therapies involving alternative immune cells are currently being developed, such as CAR-natural killer, CAR-T regulatory (Treg), CAR-macrophages (Ms), and others, each offering distinct biological advantages and potential for broader applications. Beyond oncology, CAR approaches are being explored for autoimmune diseases, infectious diseases, and fibrosis, expanding their therapeutic scope. Manufacturing complexities and safety concerns related to gene modification also highlight the need for scalable, safe production methods, including non-viral gene delivery systems. This review summarizes the evolution, current applications, and future prospects of CAR-based therapies, emphasizing the importance of ongoing innovation to enhance specificity, safety, and clinical efficacy across diverse disease contexts.
基于嵌合抗原受体的免疫疗法已经改变了癌症治疗，尤其是对于急性淋巴细胞白血病和弥漫性大B细胞淋巴瘤等血液系统恶性肿瘤。从依赖CD3ζ信号传导的第一代构建体到具有共刺激结构域的下一代嵌合抗原受体，其设计创新增强了T细胞的持久性和抗肿瘤功效。尽管取得了这些成功，但将嵌合抗原受体T细胞疗法应用于实体瘤仍面临重大挑战，包括抗原异质性、免疫抑制性肿瘤微环境以及诸如细胞因子释放综合征和神经毒性等毒性。为了克服这些障碍，目前正在开发涉及替代免疫细胞的嵌合抗原受体疗法，如嵌合抗原受体自然杀伤细胞、嵌合抗原受体调节性T细胞、嵌合抗原受体巨噬细胞等，每种疗法都具有独特的生物学优势和更广泛应用的潜力。除了肿瘤学领域，嵌合抗原受体方法也正在被探索用于自身免疫性疾病、传染病和纤维化疾病，从而扩大了它们的治疗范围。与基因修饰相关的制造复杂性和安全问题也凸显了对可扩展、安全生产方法的需求，包括非病毒基因递送系统。本综述总结了基于嵌合抗原受体疗法的发展、当前应用和未来前景，强调了持续创新对于在不同疾病背景下提高特异性、安全性和临床疗效的重要性。
