Hardwired and rewired: Tissue macrophages in homeostasis and cancer

Macrophages are highly heterogeneous innate immune cells that populate virtually all tissues, in which they acquire distinct phenotypes and homeostatic functions shaped by their local environment. Although these cells can arise from either embryonic precursors or circulating monocytes, their ultimate identity reflects an interplay between developmentally encoded transcriptional programs and tissue-derived extrinsic cues. Using selected tissue-resident macrophage subsets as examples, we highlight how environmental signals activate specialized transcriptional modules layered upon a conserved ontogenetic framework to generate the remarkable diversity of macrophage states. We further summarize tissue-specific roles of macrophages and briefly consider how these context-dependent programs influence cancer biology.