Abstract 7280: Pan-cancer single-cell RNA sequencing analysis refines multiorigin monocyte and macrophage lineages

Abstract 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. Citation Format: Truc Do Nguyen, Andrew J. Lee, Hyun Jung Park, Nameeta Shah, Bayrta Mandzhieva, Dong-Sup Lee, Inkyung Jung, Woong-Yang Park. Pan-cancer single-cell RNA sequencing analysis refines multiorigin monocyte and macrophage lineages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7280.