Targetable axes of tumor-associated macrophages: An MSF framework for precision immunotherapy

Abstract

Tumor-associated macrophages (TAMs) are a central component of the tumor microenvironment and exert dual, context-dependent effects on cancer progression. This review synthesizes the mechanisms that govern TAM polarization, their bidirectional crosstalk with tumor and stromal cells, and the consequences of metabolic reprogramming. Molecular and metabolic circuits that shape TAM phenotypes and sustain immune suppression are highlighted, and therapeutic strategies targeting TAM checkpoints, metabolism, and lineage pathways are summarized. To integrate immunometabolism with single-cell and spatial profiling, we introduce a Metabolic-Spatial-Functional Axis that links dominant metabolic programs, anatomic niches, and measurable effector functions. This framework organizes TAM heterogeneity and prioritizes biomarker-guided therapeutic combinations with clear translational readouts. Collectively, these advances support precision approaches that reprogram or constrain TAMs to enhance antitumor immunity and overcome therapeutic resistance.