Pan-cancer single-cell RNA sequencing analysis refines multiorigin monocyte and macrophage lineages

Tumor-associated macrophages (TAMs) are central regulators of tumor progression, influencing tissue homeostasis, immune suppression, and angiogenesis. To define their diversity and developmental organization across human cancers, we analyzed a unified single‑cell and spatial transcriptomic atlas of myeloid cells from healthy tissues and multiple tumor types. This analysis delineated two principal trajectories of tumor-associated macrophages (TAMs): a resident macrophage-aligned C1QC⁺ lineage and a monocyte-derived lineage comprising SPP1⁺ and ISG15⁺ TAMs. We further identified THBS1⁺ immature myeloid cells as a precursor population that transitions toward the SPP1⁺ TAM state and underlies a strongly immunosuppressive and pro-angiogenic program. Clinically, enrichment of C1QC⁺ TAMs was associated with more favorable outcomes, whereas activation of the THBS1⁺ MDSC-SPP1⁺ TAM axis correlated with poor survival and diminished response to immunotherapy. These findings refine the developmental framework of myeloid cells in cancer and underscore a pathogenic macrophage trajectory with potential therapeutic relevance.