Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche
Issued Date
2025-01-01
Resource Type
ISSN
15356108
eISSN
18783686
Scopus ID
2-s2.0-105024313912
Pubmed ID
41349542
Journal Title
Cancer Cell
Rights Holder(s)
SCOPUS
Bibliographic Citation
Cancer Cell (2025)
Suggested Citation
Guo W., Luan J., Huang X., Leon D., Gang S., Nicholson B., Bertacchi B., Bolotin D., Lingen M.W., Pearson A.T., Izumchenko E., Rosenberg A.J., Agrawal N., Vokes E.E., Punyawatthananukool S., Narumiya S., Gunzer M., Ballesteros I., Hidalgo A., Miao Y. Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche. Cancer Cell (2025). doi:10.1016/j.ccell.2025.11.001 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/113556
Title
Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche
Author's Affiliation
The University of Chicago
Yale School of Medicine
Universitätsklinikum Essen
Universidad Carlos III de Madrid
Graduate School of Medicine
Siriraj Hospital
Department of Medicine, The University of Chicago
Centro Nacional de Investigaciones Cardiovasculares Carlos III
Leibniz-Institut für Analytische Wissenschaften
Department of Pathology, The University of Chicago
Ben May Department for Cancer Research
Chan Zuckerberg Biohub Chicago
Yale School of Medicine
Universitätsklinikum Essen
Universidad Carlos III de Madrid
Graduate School of Medicine
Siriraj Hospital
Department of Medicine, The University of Chicago
Centro Nacional de Investigaciones Cardiovasculares Carlos III
Leibniz-Institut für Analytische Wissenschaften
Department of Pathology, The University of Chicago
Ben May Department for Cancer Research
Chan Zuckerberg Biohub Chicago
Corresponding Author(s)
Other Contributor(s)
Abstract
The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2<sup>High</sup> tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E<inf>2</inf> (PGE<inf>2</inf>) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.