Metabolism drives macrophage heterogeneity in the tumor microenvironment.

Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment (TME). However, the relationship between the phenotype and metabolic pattern of TAMs remains poorly understood. We performed single-cell transcriptome profiling on hepatic TAMs from mice bearing liver metastatic tumors. We find that TAMs manifest high heterogeneity at the levels of transcription, development, metabolism, and function. Integrative analyses and validation experiments indicate that increased purine metabolism is a feature of TAMs with pro-tumor and terminal differentiation phenotypes. Like mouse TAMs, human TAMs are highly heterogeneous. Human TAMs with increased purine metabolism exhibit a pro-tumor phenotype and correlate with poor therapeutic efficacy to immune checkpoint blockade. Altogether, our work demonstrates that TAMs are developmentally, metabolically, and functionally heterogeneous and purine metabolism may be a key metabolic feature of a pro-tumor macrophage population.