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

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Tumor-associated macrophages (TAMs) are key myeloid cells in the digestive system tumor microenvironment, known for plasticity and heterogeneity.
• Traditional TAM classification (M1/M2) is inadequate for capturing dynamic states across diverse tumor types and stages.
• Single-cell and spatial omics reveal TAM spatial organization is critical in gastric, colorectal, liver, and pancreatic cancers.

Purpose of the Study:

• To review TAM spatial organization and heterogeneity in digestive system tumors.
• To establish a spatial-niche framework for understanding TAM function and context-dependent states.
• To link TAM spatial distribution to metabolic adaptation, tissue remodeling, and immune regulation.

Main Methods:

• Synthesis of current evidence on TAM distribution, phenotypes, and functions across six spatial niches.
• Analysis of TAM heterogeneity reflecting dynamic functional states shaped by local microenvironmental factors.
• Integration of omics data to link spatial niches with molecular programs and functional axes.

Main Results:

• TAM heterogeneity is better understood through dynamic functional states within specific spatial niches rather than fixed subtypes.
• Six recurrent spatial contexts (hypoxic core, invasive front, etc.) influence TAM distribution and function.
• A niche-to-function framework highlights TAM roles in metabolic adaptation, tissue remodeling, and immune regulation.

Conclusions:

• A spatial-niche framework provides a context-sensitive approach to TAM heterogeneity in digestive cancers.
• Understanding niche-specific TAM reprogramming is essential for effective cancer treatment strategies.
• This framework can guide rational combinations of therapies, including immunotherapy, for improved patient outcomes.