CAR macrophages with built-In CD47 blocker combat tumor antigen heterogeneity and activate T cells via cross-presentation

Siqi Chen, Yingyu Wang, Jessica Dang, Nuozi Song, Xiaoxin Chen, Jinhui Wang, Guo N. Huang, Christine E. Brown, Jianhua Yu, Irving L. Weissman, Steven T. Rosen and Mingye Feng ()
Additional contact information
Siqi Chen: City of Hope
Yingyu Wang: City of Hope National Medical Center
Jessica Dang: City of Hope
Nuozi Song: City of Hope
Xiaoxin Chen: San Francisco
Jinhui Wang: City of Hope
Guo N. Huang: San Francisco
Christine E. Brown: City of Hope
Jianhua Yu: City of Hope
Irving L. Weissman: Stanford Medicine
Steven T. Rosen: City of Hope National Medical Center
Mingye Feng: City of Hope

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Macrophage-based cancer cellular therapy has gained substantial interest. However, the capability of engineered macrophages to target cancer heterogeneity and modulate adaptive immunity remains unclear. Here, exploiting the myeloid antibody-dependent cellular phagocytosis biology and phagocytosis checkpoint blockade, we report the enhanced synthetic phagocytosis receptor (eSPR) that integrate FcRγ-driven phagocytic chimeric antigen receptors (CAR) with built-in secreted CD47 blockers. The eSPR engineering empowers macrophages to combat tumor antigen heterogeneity. Transduced by adenoviral vectors, eSPR macrophages are intrinsically pro-inflammatory imprinted and resist tumoral polarization. Transcriptomically and phenotypically, eSPR macrophages elicit a more favorable tumor immune landscape. Mechanistically, eSPR macrophages in situ stimulate CD8 T cells via phagocytosis-dependent antigen cross-presentation. We also validate the functionality of the eSPR system in human primary macrophages.

Date: 2025
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DOI: 10.1038/s41467-025-59326-9

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