Cao Qi, Wang Yiping, Chen Jianwei, Wang Ruifeng, Chen Titi, Gloss Brian, Read Scott A, Wang Xuerong, Lee Vincent W S, Clancy Leighton, Rogers Natasha M, Alexander Stephen I, Zheng Guoping, Yu Di, Harris David C H
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
Department of Renal Medicine, Westmead Hospital, Sydney, New South Wales, Australia.
Nat Biomed Eng. 2025 May 7. doi: 10.1038/s41551-025-01387-8.
Chimeric antigen receptor (CAR) T-cell immunotherapy has shown great success in clinical cancer, bringing hope to apply CAR strategies to other clinical settings. Here we developed a CAR macrophage (CAR-M) that recognizes the major inflammatory molecule tumour necrosis factor (TNF) and activates an intracellular IL-4 signalling pathway, thereby programming engineered macrophages for an anti-inflammatory function. CAR-M therapy has exhibited efficacy in mouse models of both acute and chronic inflammatory diseases. In kidney ischaemia reperfusion injury (IRI), infused CAR-Ms switched to an anti-inflammatory phenotype in inflamed kidney and attenuated kidney IRI. The anti-inflammatory phenotype of infused CAR-Ms switched off during the recovery phase of kidney IRI, coinciding with the disappearance of TNF. In Adriamycin-induced nephropathy, a model of chronic inflammatory disease, infused CAR-Ms maintained an anti-inflammatory phenotype for several weeks in response to sustained high levels of TNF and improved kidney function and structure. CAR-Ms also effectively reduced tissue injury in another organ, the liver. Human anti-TNF CAR-Ms exhibit anti-inflammatory phenotype and function in response to TNF. The CAR-M design, using signal switching, holds promise for the treatment of a broad range of acute and chronic inflammatory diseases.
嵌合抗原受体（CAR）T细胞免疫疗法在临床癌症治疗中取得了巨大成功，为将CAR策略应用于其他临床领域带来了希望。在此，我们开发了一种能够识别主要炎症分子肿瘤坏死因子（TNF）并激活细胞内白细胞介素-4信号通路的CAR巨噬细胞（CAR-M），从而使工程化巨噬细胞具备抗炎功能。CAR-M疗法在急慢性炎症疾病的小鼠模型中均显示出疗效。在肾脏缺血再灌注损伤（IRI）中，注入的CAR-Ms在炎症肾脏中转变为抗炎表型，减轻了肾脏IRI。注入的CAR-Ms的抗炎表型在肾脏IRI的恢复阶段关闭，这与TNF的消失相一致。在阿霉素诱导的肾病（一种慢性炎症疾病模型）中，注入的CAR-Ms因持续高水平的TNF而在数周内维持抗炎表型，并改善了肾功能和结构。CAR-Ms还有效减轻了另一器官肝脏的组织损伤。人源抗TNF CAR-Ms在接触TNF时表现出抗炎表型和功能。利用信号转换的CAR-M设计有望用于治疗多种急慢性炎症疾病。
