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

Author

Listed:
  • 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
    San Francisco)

  • Jinhui Wang

    (City of Hope)

  • Guo N. Huang

    (San Francisco
    San Francisco)

  • Christine E. Brown

    (City of Hope
    Department of Hematology and Hematopoietic Cell Transplantation, City of Hope)

  • Jianhua Yu

    (City of Hope
    City of Hope National Medical Center
    Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
    City of Hope)

  • Irving L. Weissman

    (Stanford Medicine
    Stanford Medicine)

  • Steven T. Rosen

    (City of Hope National Medical Center
    Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
    City of Hope)

  • Mingye Feng

    (City of Hope)

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.

Suggested Citation

  • 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 & Mingye Feng, 2025. "CAR macrophages with built-In CD47 blocker combat tumor antigen heterogeneity and activate T cells via cross-presentation," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59326-9
    DOI: 10.1038/s41467-025-59326-9
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