Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy
- Cell. 2026 Jun 19:S0092-8674(26)00643-4. doi: 10.1016/j.cell.2026.05.043.
- 1. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- 2. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
- 3. Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE, USA.
- 4. Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
- 5. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.
- 6. Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA; Department of Clinical Computational Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- 7. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: [email protected].
Engineered Macrophages are promising for tumor immunotherapy but are limited by poor ex vivo expansion, genetic tractability, and biodistribution after transfer. Here, we develop defined culture conditions that enable long-term expansion of mouse and human granulocyte-monocyte progenitors (GMPs) while preserving progenitor identity and myeloid potential, establishing GMPs as a renewable engineering platform. Mechanistically, we identify myeloperoxidase as a regulator of GMP proliferation. Expanded GMPs are readily engineered and, after transfer, seed hematopoietic niches and generate donor-derived myelopoiesis that restores Antibacterial defense in chronic granulomatous disease mice and yields abundant tumor-infiltrating Macrophages. GMPs engineered with chimeric antigen receptors (CARs) suppress CD19-positive leukemia and human epidermal growth factor receptor 2 (HER2)-positive solid Tumors. We further introduce a CAR incorporating an immunoglobulin G (IgG) Fc domain that recruits host Fc receptor-expressing phagocytes, enables T cell priming across major histocompatibility complex (MHC) mismatch, and enhances efficacy in immunocompetent allogeneic Cancer Models. Together, these findings establish expandable GMPs as a scalable platform for engineered immunotherapy.