Language

English

Publication Date

5-28-2026

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-25-3935

PMID

42207963

PMCID

PMC13293467

PubMedCentral® Posted Date

6-25-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Neutrophils are a prominent component of the tumor microenvironment that can have both pro- and anti-tumor functions. By analyzing neutrophils across different human cancers, we revealed an ICAM1high subset enriched in the tumor microenvironment, which were 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 and macrophage-enriched, mesenchymal-like ecosystems. As ICAM1high neutrophils can reverse migrate from tissue into the circulation, the adhesive and reverse migratory properties together mediated metastatic intravasation. Spatial transcriptomic and tissue microarray analyses demonstrated interactions between tumor cells, neutrophils, and endothelial cells in human TNBC, particularly in non-Hispanic European compared to African American patients. Together, this study demonstrated tumor-immune co-evolution in which neutrophils instruct phenotypes and metastatic behaviors of TNBC, which may preferentially occur in patients of certain ancestries.

Published Open-Access

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