Engineered macrophages hold great promise for cancer immunotherapy, but they’re limited by in vitro expansion, genetic tractability, and post-transplant distribution. We developed defined culture conditions that allow mouse and human granulocyte-monocyte progenitors (GMPs) to expand long-term while maintaining their progenitor identity and myeloid potential, establishing GMPs as a renewable engineering platform. Mechanistically, we identified myeloperoxidase as a regulator of GMP proliferation. Expanded GMPs are easy to engineer, can seed hematopoietic niches after transfer, generate donor-derived myeloid cells, restore antibacterial defense in chronic granulomatous mice, and produce abundant tumor-infiltrating macrophages. GMPs designed with chimeric antigen receptors (CARs) suppress CD19-positive leukemia and human HER2-positive solid tumors. We further introduced a CAR containing an IgG Fc domain, which recruits host Fc receptor-expressing phagocytes, enabling MHC-unmatched T cell triggering and improving efficacy in immune-competent allogeneic cancer models. Altogether, these findings establish expandable GMPs as a scalable platform for engineered immunotherapy.

Reference Information

Cell (IF 45.1)

Pub Date: 2026-06-19
DOI: 10.1016/j.cell.2026.05.043

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