Targeting inflammation with chimeric antigen receptor macrophages using a signal switch

Qi Cao; Yiping Wang; Jianwei Chen; Ruifeng Wang; Titi Chen; Brian Gloss; Scott A Read; Xuerong Wang; Vincent W S Lee; Leighton Clancy; Natasha M Rogers; Stephen I Alexander; Guoping Zheng; Di Yu; David C H Harris

doi:10.1038/s41551-025-01387-8

Targeting inflammation with chimeric antigen receptor macrophages using a signal switch

Nat Biomed Eng. 2025 May 7. doi: 10.1038/s41551-025-01387-8. Online ahead of print.

Authors

Qi Cao^#¹, Yiping Wang^#², Jianwei Chen², Ruifeng Wang², Titi Chen^{2

3}, Brian Gloss⁴, Scott A Read⁵, Xuerong Wang², Vincent W S Lee^{2

3}, Leighton Clancy^{6

7}, Natasha M Rogers^{2

3}, Stephen I Alexander⁸, Guoping Zheng², Di Yu⁹, David C H Harris^{10

11}

Affiliations

¹ Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia. qi.cao@sydney.edu.au.
² Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
³ Department of Renal Medicine, Westmead Hospital, Sydney, New South Wales, Australia.
⁴ Westmead Research Hub, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
⁵ Storr Liver Centre, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
⁶ Blood Transplant and Cell Therapies Laboratory, NSW Health Pathology-ICPMR Westmead, Sydney, New South Wales, Australia.
⁷ Bone Marrow Transplant & Cell Therapies, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
⁸ Centre for Kidney Research, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
⁹ Faculty of Medicine, The University of Queensland Diamantina Institute, St Lucia, Queensland, Australia.
¹⁰ Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia. david.harris@sydney.edu.au.
¹¹ Department of Renal Medicine, Westmead Hospital, Sydney, New South Wales, Australia. david.harris@sydney.edu.au.

^# Contributed equally.

PMID: 40335685
DOI: 10.1038/s41551-025-01387-8

Abstract

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.

Abstract

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