CCL3 is produced by aged neutrophils across cancers and promotes tumor growth PMID: 41650972

ADC Targets in Oncology

2026-04-10

CCL3 is produced by aged neutrophils across cancers and promotes tumor growth

Cancer Cell. 2026 Mar 9;44(3):624-640.e12. doi: 10.1016/j.ccell.2026.01.006.

Evangelia Bolli ¹ , Pratyaksha Wirapati ¹ , Mehdi Hicham ¹ , Yuxuan Xie ¹ , Marie Siwicki ² , Florent Duval ¹ , Anne-Gaëlle Goubet ¹ , Máté Kiss ¹ , Béatrice Zitti ¹ , Thomas Zwahlen ³ , Sheri Mcdowell ¹ , Ruben Bill ⁴ , Simona Angerani ⁵ , Camilla Engblom ⁶ , Seth Anderson ⁷ , Aiping Jiang ⁷ , Oliver Hartley ⁵ , David B Sykes ⁸ , Maja Jankovic ⁹ , Nadine Fournier ¹⁰ , Matthias Gunzer ¹¹ , David Tarussio ¹² , Stéphanie Tissot ¹² , Peter M Sadow ¹³ , William C Faquin ¹³ , Moshe Sade-Feldman ¹⁴ , Ralph Weissleder ¹⁵ , Sara Pai ¹⁶ , François Mercier ⁹ , Robert Manguso ¹⁴ , Mikaël J Pittet ¹⁷

Affiliations

1. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Translational Research Center in Oncohaematology, University of Geneva, Geneva, Switzerland.
2. Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
3. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Translational Research Center in Oncohaematology, University of Geneva, Geneva, Switzerland; Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland; Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
4. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
5. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
6. SciLifeLab, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
7. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
8. Mass General Brigham Cancer Center, Boston, MA, USA.
9. Lady Davis Institute for Medical Research, McGill University, Montréal, Quebec, Canada.
10. Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland; Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
11. Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Leibniz-Institut für Analytische Wissenschaften ISAS -e.V., Dortmund, Germany.
12. Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
13. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Mass General Brigham, Harvard Medical School, Boston, Massachusetts, USA.
14. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
15. Mass General Brigham Cancer Center, Boston, MA, USA; Center for Systems Biology, Massachusetts General Hospital, Cambridge St, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital, Fruit St, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Longwood Ave, Boston, MA, USA.
16. Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
17. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Translational Research Center in Oncohaematology, University of Geneva, Geneva, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland; Department of Oncology, Geneva University Hospitals (HUG), Geneva, Switzerland. Electronic address: [email protected].

Abstract

Tumor-associated neutrophils (TANs) are abundant across cancers, yet their phenotypic diversity and functional states remain poorly defined. Here, we introduce a cell-type probability classifier that recovers low-transcript neutrophils from scRNAseq datasets, enabling pan-cancer analyses of TAN heterogeneity. Across >190 human and murine tumors, we identify a conserved differentiation trajectory that culminates in a terminal CCL3^hi state. This state exhibits pro-tumor transcriptional programs, including those involved in hypoxic adaptation and senescence. Consistently, CCL3^hi TANs are enriched in hypoxic tumor niches in both humans and mice. Through mechanistic perturbations of neutrophil-derived CCL3 in mice, we show that it sustains TAN survival in hypoxic tumor regions via CCR1-dependent signaling. These findings establish CCL3 as a conserved marker and functional driver of pro-tumor neutrophils in growing tumors, and provide a scalable framework for dissecting neutrophil biology across Cancer types.

Keywords

CCL3-CCR1 signaling; CRISPR perturbation; hypoxia; neutrophil aging; neutrophil differentiation; neutrophil heterogeneity; pan-cancer analysis; single-cell RNA sequencing; tumor microenvironment; tumor-promoting neutrophils.