CCL3 is produced by aged neutrophils across cancers and promotes tumor growth
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<sup>hi</sup> state. This state exhibits pro-tumor transcriptional programs, including those involved in hypoxic adaptation and senescence. Consistently, CCL3<sup>hi</sup> 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.
Authors
- Evangelia Bolli (ORCID: https://orcid.org/0000-0002-2012-8314)
- Marie Siwicki (ORCID: https://orcid.org/0000-0001-6330-8780)
- David Tarussio
- Sheri A. C. McDowell (ORCID: https://orcid.org/0000-0002-3155-8547)
- Nadine Fournier (ORCID: https://orcid.org/0000-0002-9347-7929)
- Mehdi Hicham (ORCID: https://orcid.org/0000-0002-9979-4757)
- William C. Faquin (ORCID: https://orcid.org/0000-0002-9043-7171)
- Sara I. Pai (ORCID: https://orcid.org/0000-0002-6341-9971)
- Pratyaksha Wirapati (ORCID: https://orcid.org/0000-0002-0327-4686)
- Simona Angerani (ORCID: https://orcid.org/0000-0003-2006-539X)
- Sarah R. Philips (ORCID: https://orcid.org/0000-0003-3197-779X)
- Béatrice Zitti (ORCID: https://orcid.org/0000-0003-4610-7535)
- François Mercier (ORCID: https://orcid.org/0000-0001-5324-2167)
- D. Sykes (ORCID: https://orcid.org/0000-0002-7578-890X)
- Yuxuan Xie (ORCID: https://orcid.org/0009-0006-8087-6337)
- Florent Duval
- Moshe Sade-Feldman
- Máté Kiss
- Ralph Weissleder
- Camilla Engblom
- Ruben Bill
- Maja Jankovic
- Oliver Hartley
- Seth Anderson
- Peter M. Sadow
- Stéphanie Tissot
- Matthias Gunzer
- Aiping Jiang
- Thomas Zwahlen
- Robert Manguso
Institutions
- Broad Institute (US)
- University of Geneva (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- Karolinska University Hospital (SE)
- University of Calgary (CA)
- University Hospital of Bern (CH)
- Yale University (US)
- Massachusetts General Hospital (US)
- Ludwig Cancer Research (CH)
- Essen University Hospital (DE)
- Swiss Cancer Center Léman (CH)
- Center for Cancer Research (US)
- Center for Systems Biology (US)
- McGill University (CA)
- University of Duisburg-Essen (DE)
- University of Lausanne (CH)
Publication Details
- Journal
- Cancer Cell
- Published
- 2026-02-05
- DOI
- https://doi.org/10.1016/j.ccell.2026.01.006
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 24.43