ICAM1high Neutrophils Sculpt Tumor Evolution and Metastasis through Symbiotic Adhesion and Reverse Migration

  • Cancer Res. 2026 May 28:10.1158/0008-5472.CAN-25-3935. doi: 10.1158/0008-5472.CAN-25-3935.
Ling Wu  1 ,  Zhan Xu  1 ,  Jun Wang  1 ,  Fengshuo Liu  1 ,  Yunfeng Ding  1 ,  Yang Gao  2 ,  Siyue Wang  1 ,  Jun Liu  1 ,  Hilda L Chan  3 ,  Weiguo Wu  4 ,  Yi-Hsuan Wu  5 ,  Liqun Yu  1 ,  Xiaoxin Hao  6 ,  Xuan Li  1 ,  David G Edwards  3 ,  Cher Sha  1 ,  Tobie D Lee  1 ,  Nan Guan  3 ,  Sergio Aguirre  5 ,  Luis Becerra-Dominguez  1 ,  Dane Hoffman  1 ,  Xiang Chen  1 ,  Charlotte Helena Rivas  1 ,  Xiaoyuan G Yan  7 ,  Igor L Bado  8 ,  Weijie Zhang  9 ,  Qian Zhu  4 ,  Arun Sreekumar  3 ,  Robert L Satcher  10 ,  Xiang H-F Zhang  1
Affiliations
  • 1. Baylor College of Medicine Houston, TX United States.
  • 2. The Ohio State University Columbus, Ohio United States.
  • 3. Baylor College of Medicine Houston, Texas United States.
  • 4. Baylor College of Medicine United States.
  • 5. Baylor College of Medicine Houston United States.
  • 6. Baylor College of Medicine Suzhou, Jiangsu China.
  • 7. The Awty International School Houston, Texas United States.
  • 8. Icahn School of Medicine at Mount Sinai New York United States.
  • 9. Baylor College of Medicine Hangzhou, Zhejiang China.
  • 10. The University of Texas MD Anderson Cancer Center Houston, TX United States.
PMID: 42207963 DOI: 10.1158/0008-5472.CAN-25-3935
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.

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