Abstract As crucial phagocytes of the innate immune system, macrophages (M ϕ s) protect mammalian hosts, maintain tissue homeostasis and influence disease pathogenesis. Nonetheless, M ϕ s are susceptible to various pathogens, including bacteria, viruses and parasites, which cause various infectious diseases, necessitating a deeper understanding of pathogen–M ϕ interactions and therapeutic insights. Pluripotent stem cells (PSCs) have been efficiently differentiated into PSC‐derived M ϕ s (PSCdM ϕ s) resembling primary M ϕ s, advancing the modelling and cell therapy of infectious diseases. However, the mass production of PSCdM ϕ s, which lack proliferative capacity, relies on large‐scale expansions of PSCs, thereby increasing both costs and culture cycles. Notably, M ϕ s deficient in the MafB/c‐Maf genes have been reported to re‐enter the cell cycle with the stimulation of specific growth factor cocktails, turning into self‐renewing M ϕ s (SRM ϕ s). This review summarizes the applications of PSCdM ϕ s in the modelling and cell therapy of infectious diseases and strategies for establishing SRM ϕ s. Most importantly, we innovatively propose that PSCs can serve as a gene editing platform to creating PSC‐derived SRM ϕ s (termed PSRM ϕ s), addressing the resistance of M ϕ s against genetic manipulation. We discuss the challenges and possible solutions in creating PSRM ϕ s. In conclusion, this review provides novel insights into the development of physiologically relevant and expandable M ϕ models, highlighting the enormous potential of PSRM ϕ s as a promising avenue for the modelling and cell therapy of infectious diseases.
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