Significance: Tumor progression is supported by non-cancerous stromal cells, of which tumor-associated macrophages (TAMs) are prominent constituents. These cells could be considered promising therapeutic targets, but this requires a better understanding of their heterogeneity under the influence of tumor microenvironmental cues and/or ontogenic differences. Recent Advances: The availability of oxygen is an important regulator of the TAM phenotype, as well as of its access to myelopoietic growth factors. Very recent evidence also demonstrated that macrophages can be derived from embryonal precursors or from monocytes post-birth, introducing yet another level of heterogeneity among macrophages. Critical Issues: The relative contribution of ontogenically distinct macrophages to tumor characteristics is, to a large extent, still an open question. In addition, further knowledge on the role of tumor microenvirontal cues that shape TAMs is warranted. Future Directions: More detailed insights into the TAM-regulating factors will provide new opportunities for therapeutic intervention. Interference with the phenotypes of TAM, which are known to be immunosuppressive and to contribute to dysfunctional tumor blood vessels, is anticipated to be beneficial in combination with chemotherapy and/or immunotherapy. Antioxid. Redox Signal. 25, 775–791.
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