Induced pluripotent stem cell-derived macrophages (iMacs) in translational medicine: Disease models, drug testing, and therapeutic applications

Macrophages play key roles in innate immunity, inflammation, and homeostasis. However, conventional macrophage models, particularly primary macrophages derived from donor monocytes (MDMs), are limited by donor-to-donor variability, limited proliferative capacity and non-renewable nature, low scalability, and poor genetic tractability. Induced pluripotent stem cell-derived macrophages (iMacs) have emerged as an alternative that offers a renewable source of engineered human macrophages. This review summarizes the approaches used to generate and characterize iMacs, highlighting their functional properties such as phagocytosis, efferocytosis, cytokine secretion, lipid metabolism, and macrophage polarization. We then focus on translational applications of iMacs in three important areas: (i) disease modeling, where iMacs enable large-scale production, precise genetic modification, and accurately mimic host-pathogen interactions, autoimmune phenotypes, metabolic inflammation, and tissue-specific macrophage functions; (ii) drug discovery, where the combination of large-scale production and assay miniaturization allows high-content and high-throughput screening with increased physiological accuracy over immortalized cell lines; and (iii) therapeutics, which comprise engineered iMac-based therapies and novel cell therapy approaches for various infectious, genetic, and inflammatory diseases. Finally, we discuss current challenges and opportunities in developing iMacs toward clinical applications. Overall, iMacs are a versatile bridge between mechanistic immunology and next-generation translational medicine.