Data from Pan-Cancer Single-Cell RNA Sequencing Analysis Refines Multi-Origin Monocyte and Macrophage Lineages

Abstract Tumor-associated macrophages (TAM) play a crucial and important role in cancer dynamics by affecting homeostasis, immunosuppression, and angiogenesis within the tumor microenvironment. Using single-cell transcriptomics, we constructed a comprehensive atlas of myeloid cell populations across healthy and pan-cancer tissues that revealed heterogeneity. Our analysis suggested that TAMs may arise from two distinct origins: C1QC+ TAMs, which likely are derived from resident tissue macrophages, and SPP1+ TAMs and ISG15+ TAMs, which seem to originate from circulating monocytes. Regarding immature myeloid-derived suppressor cells (MDSC), we highlighted THBS1+ MDSCs and their descendants, SPP1+ TAMs, as key contributors to tumor progression, immunosuppression, and angiogenesis. We proposed a dichotomous model for TAMs, in which C1QC+ TAMs are associated with better patient outcomes, whereas the THBS1+ MDSC–SPP1+ TAM lineage correlates with poorer survival and unfavorable response to immunotherapy. This study offers insight into the complex interactions among monocyte–macrophage subtypes and sheds light on TAM heterogeneity and its implications for cancer progression and therapeutic strategies.