Tumor-associated macrophages: Ontogeny, plasticity, spatial ecosystems, and therapeutic targeting.

Abstract

Accumulating evidence demonstrates that tumor-associated macrophages (TAMs) are central regulators of cancer progression rather than passive components of tumor inflammation. Advances in single-cell and spatial technologies have revealed that macrophages actively shape tumor initiation, growth, immune evasion, angiogenesis, and metastasis through context-dependent programs governed by developmental origin, microenvironmental cues, metabolic constraints, and epigenetic remodeling. Tumors exploit the inherent plasticity of macrophages, reprogramming them into diverse functional states that support malignant expansion and therapeutic resistance. This chapter provides an integrated framework for understanding TAM biology across multiple regulatory dimensions, including ontogeny, plasticity, metabolism, epigenetic control, and spatial niche organization. We examine how embryonic-derived and monocyte-derived macrophages acquire distinct identities, how tumor ecosystems sculpt macrophage behavior through cytokine, metabolic, and mechanical signals, and how spatial localization within tumors generates specialized macrophage subsets with nonredundant functions. Emerging insights from spatial transcriptomics, intravital imaging, and multiomic profiling are discussed as transformative tools that redefine macrophage classification and function in human cancer. Finally, we synthesize current and emerging therapeutic strategies targeting TAM recruitment, survival, reprogramming, and phagocytic function, including metabolic and epigenetic interventions, immune checkpoint modulation, and macrophage-engineered cell therapies. By integrating mechanistic biology with translational and clinical perspectives, this chapter highlights tumor-associated macrophages as programmable determinants of tumor behavior and as critical targets for next-generation precision oncology.