AbstractInflammatory cells are a vital component of the tumor stroma and, of these, tumor-associated macrophages (TAM) are the major cell type. TAMs are recruited early in tumorigenesis and generally promote metastasis, stimulate tumor angiogenesis, and drive immunosuppression. TAMs have been shown to express the endothelial cell markers that enable chemotaxis and proangiogenic capacity. In this issue of Cancer Research, Jakab and colleagues challenge the functional significance of Tie2-expressing monocytes/macrophages (TEM) in the context of tumor growth and progression. By employing myeloid-specific deletion of the angiopoietin receptor Tie2 and comprehensive analysis of myeloid cell single-cell RNA sequencing datasets, they provide compelling data that Tie2-positive macrophages do not contribute to tumor angiogenesis or relapse after chemotherapy, two major biologic processes previously attributed to tumor-associated TEMs. The study highlights that the concept of macrophage-expressed Tie2 as a therapeutic target or prognostic indicator needs reconsideration.See related article by Jakab et al., p. 1353