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

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.