Spatial single-cell landscape of tumor-associated macrophages and their crosstalk with the tumor microenvironment

Abstract Tumor-associated macrophages (TAMs) constitute a critical immune cell population within the tumor microenvironment (TME) and exhibit high functional heterogeneity. In this study, a pan-cancer atlas comprising 28 TAM subtypes was systematically constructed by integrating single-cell transcriptomic and spatial transcriptomic data from 291 human samples across 16 cancer types. The biological characteristics and spatial distribution patterns of these subtypes within the TME as well as the interaction mechanisms between TAMs and TME components closely associated with tumor progression were elucidated. TAMs localized in the peritumoral or core regions of tumors participate in angiogenesis and metabolic reprogramming, promoting further tumor development. The retention of CD8 + T cells by TAMs can induce local inflammation and an immunosuppressive microenvironment. Additionally, cancer-associated fibroblasts (CAFs) play crucial roles in the polarization and survival of TAMs and are involved in their recruitment and activation. TAMs facilitate tumor invasion, metastasis and immune evasion through secreted phosphoprotein 1 (SPP1) and interaction with the integrin family/CD44 axis in CAFs. This study deepens the understanding of the biological characteristics of TAMs and provides new theoretical foundations and potential targets for cancer treatment strategies targeting specific TAM subpopulations.