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In tumor immunotherapy applications, CAR-engineered GMP can differentiate into tumor-infiltrating macrophages and exert antigen-specific anti-tumor effects in CD19-positive leukemia and HER2-positive solid tumor xenograft models. To overcome the bottleneck in allogeneic infusion where host T cells cannot be effectively activated by donor cells due to MHC mismatch, the authors designed a chimeric antigen receptor-Fc (CAR-Fc) structure, inserting an IgG1 Fc domain between the conventional CAR extracellular and transmembrane regions. This design not only retains CAR-mediated direct phagocytosis but also recruits nearby host phagocytes through Fc receptors to cooperatively engulf target cells, thereby presenting tumor antigens to host T cells and activating antigen-specific immune responses. In MHC-mismatched immunocompetent mouse models of lymphoma and breast cancer, CAR-Fc-GMP significantly delayed tumor progression and extended survival compared to conventional CAR-GMP. This work uses expandable myeloid progenitor cells as an engineered cell platform and combines Fc-mediated recruitment of host immunity, providing a new paradigm for overcoming the immune barrier in allogeneic cell therapy.
Reference:
DOI: 10.1016/j.cell.2025.11.020
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