Tumor-associated macrophages (TAMs) play vital roles in cancer tissue homeostasis, immunosuppression, and angiogenesis in the tumor microenvironment. Here, we utilize single-cell transcriptomics to present an atlas of healthy and pan-cancer myeloid cell populations, revealing their remarkable heterogeneity. We uncovered the dual origins of TAMs including C1QC+ TAMs derived from resident tissue macrophages, and SPP1+ TAMs and ISG15+ TAMs derived from blood monocytic populations. The differentiation of immature myeloid-derived suppressor cells (MDSCs) to TAMs is also elucidated, with THBS1+ MDSCs and SPP1+ TAMs shown to play critical roles in immunosuppression and angiogenesis and are associated with worse survival in many cancer types. Additionally, this study reveals the presence of a monocytic subtype, BAG3+ Mono, that undergoes cellular stress during the differentiation into M2 macrophages and is linked to poor survival rates in multiple cancer types and inferior response to immune-checkpoint blockade (ICB) therapy. Overall, this study offers critical perspectives into the intricate interplay between various monocyte-macrophage cell subtypes.
