ICAM1high Neutrophils Sculpt Tumor Evolution and Metastasis Through Symbiotic Adhesion and Reverse Migration.

Neutrophils are a prominent component of the tumor microenvironment (TME) that can have both pro- and antitumor functions. By analyzing neutrophils across different human cancers, we revealed an ICAM1high subset enriched in the TME, which was also observed in murine triple-negative breast cancer (TNBC) models. ICAM1high neutrophils exhibited an enhanced capacity for cell-cell adhesion specifically with tumor cells retaining epithelial features, and this adhesion conferred mutual advantages to both cell types. In contrast, cancer cells with mesenchymal-like phenotypes were vulnerable to neutrophil-mediated cytotoxicity due to decreased cell adhesion and elastase resistance. These opposite effects drove tumor evolution toward a dichotomy of neutrophil-enriched, epithelial-like ecosystems and macrophage-enriched, mesenchymal-like ecosystems. As ICAM1high neutrophils can reverse migrate from tissue into the circulation, the adhesive and reverse migratory properties together mediate metastatic intravasation. Spatial transcriptomic and tissue microarray analyses demonstrated interactions between tumor cells, neutrophils, and endothelial cells in human TNBC, particularly in non-Hispanic Europeans compared with African American patients. Together, this study demonstrated tumor-immune coevolution in which neutrophils instruct the phenotypes and metastatic behaviors of TNBC, which may preferentially occur in patients of certain ancestries. SIGNIFICANCE: A distinct subset of ICAMhigh tumor-infiltrating neutrophils with increased adhesion and reverse transendothelial migration shapes tumor phenotypes and metastatic potential through mutually beneficial interactions with epithelial cancer cells.