This review highlights the hierarchical transcriptional networks that govern macrophage specification and function. We describe how lineage-determining, identity-imprinting, and tissue-specific transcription factors coordinate macrophage differentiation and specialization across organs, emphasizing the transcriptional regulation underlying macrophage diversity in health and disease.

ABSTRACT

Tissue-resident and recruited macrophages are integral to organ development, homeostasis, immunity, and disease pathogenesis. Their remarkable diversity arises from distinct developmental origins, differentiation trajectories, and microenvironmental cues that shape their identity and function. Central to these processes is transcriptional regulation. In this review, we provide a comprehensive overview of the transcription factor (TF) networks that orchestrate resident tissue macrophage (RTM) differentiation from progenitor cells, imprint core macrophage identity, and drive tissue-specific functions. We first delineate the collaborative roles of lineage-determining TFs, such as PU.1 and C/EBPs, which prime macrophage progenitors for commitment. We then examine identity-imprinting TFs that establish and maintain the core macrophage program, and tissue-specific TFs that allow integration of local niche signals to tailor RTM phenotypes across organs. While the focus is on RTMs at steady state, we also highlight how RTMs can undergo transcriptional reprogramming upon tissue perturbation, and how newly recruited macrophages may engage distinct regulatory circuits upon entering diseased tissues, with tumors serving as an example.