Spatial-Niche Perspective on the Heterogeneity and Functional Reprogramming of Tumor-Associated Macrophages in...

Tumor-associated macrophages (TAMs) are among the most important myeloid cell populations in the tumor microenvironment of digestive system tumors and are characterized by marked plasticity, heterogeneity, and context dependence. This review focuses on gastric, colorectal, liver, and pancreatic cancers as representative digestive system solid tumors in which TAM spatial organization has been increasingly characterized by single-cell and spatial omics studies. Traditional M1/M2 polarization or fixed subtype-based classification is insufficient to capture the continuous state transitions of TAMs across tumor types, disease stages, and tissue regions. Recent evidence suggests that TAM heterogeneity reflects dynamic functional states shaped within distinct spatial niches by local oxygen supply, metabolic stress, stromal architecture, vascular status, and interactions with neighboring cells. From a spatial-niche perspective, this review synthesizes current evidence on TAM distribution patterns, phenotypic changes, and functional biases across six recurrent spatial contexts: the hypoxic core, invasive front, fibrotic septa, perivascular regions, tertiary lymphoid structure (TLS)-adjacent regions, and necrotic borders. By linking these niches with cross-niche functional axes and evidence-supported molecular programs, we provide a structured niche-to-function framework for comparing TAM spatial heterogeneity and its major functional dimensions, including metabolic adaptation, tissue remodeling, and immune-inflammatory regulation. This context-sensitive framework may help guide future studies of niche-specific TAM reprogramming and rational combinations with immunotherapy and other treatment strategies.