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Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand because of a poorly organized vasculature, is often a prominent feature in solid tumors. However, to what extent tumor hypoxia regulates the TAM phenotype in vivo is unknown. Here, we show that the myeloid infiltrate in mouse lung carcinoma tumors encompasses two morphologically distinct CD11b^hiF4/80^hiLy6C^lo TAM subsets, designated as MHC-II^lo and MHC-II^hi TAM, both of which were derived from tumor-infiltrating Ly6C^hi monocytes. MHC-II^lo TAM express higher levels of prototypical M2 markers and reside in more hypoxic regions. Consequently, MHC-II^lo TAM contain higher mRNA levels for hypoxia-regulated genes than their MHC-II^hi counterparts. To assess the in vivo …