Embracing macrophage complexity for research and translation

Macrophages are among the most versatile differentiated cell types in the body, serving as key regulators of tissue development, homeostasis, inflammation, repair, and immunity. Their functional diversity cannot be captured by fixed subsets, binary activation states, or single-marker definitions. Macrophage identity emerges instead from the integration of developmental origin, tissue niche, epigenetic history, local environmental cues, and disease-associated signals. Advances in single-cell genomics, spatial profiling, epigenomics, in vivo perturbation, and computational modeling now show that this behavior is organized through modular gene programs, so that any given macrophage state is best described as a weighted combination of program activities rather than a discrete label. We argue that embracing this modular architecture matters not only for annotation but for therapy: macrophage-directed interventions will require defining disease-associated states, identifying surface-accessible entry points into them, and rewiring the underlying programs with spatial and temporal precision.