Abstract Granulocytes and macrophages are the frontline defenders of the innate immune system. These myeloid cells play a crucial role in not only eliminating pathogens and tumor cells, but also regulating adaptive immune responses. In neonatal sepsis and post-chemotherapy agranulocytosis, the absence of these cells leaves the host highly vulnerable to infections. Beyond replacement to prevent or control neutropenic sepsis, engineered myeloid cells may offer distinct opportunities for cell therapies. For example, the mobility and specific homing capacities of neutrophils to sites of inflammation could be exploited to deliver biocidal agents, or anti-inflammatory healing signals during sepsis, autoimmunity, and organ transplantation. Additionally, myeloid cells can be engineered to express chimeric antigen receptors (CAR), carry chemotherapeutics, or enhance lymphoid tumor killing. However, traditional methods of cell isolation are incapable of providing sufficient cell numbers of these short-lived cells; their propensity for premature activation further complicates their cell engineering. Here, we review current and future biotherapeutic innovations that employ engineered multipotent myeloid progenitors derived from either self-renewing human induced pluripotent stem cells (hiPSC) or primary CD34+ hematopoietic stem-progenitors. We provide a roadmap for solving the challenges of sourcing, cost, and production of engineered myeloid cell therapies.
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