CCL3 is produced by aged neutrophils across cancers and promotes tumor growth
Year: 2026
Type: article
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.
Source: Cancer Cell
Authors: Evangelia Bolli, Pratyaksha Wirapati, Mehdi Hicham, Yuxuan Xie, Marie Siwicki, Florent Duval, Anne-Gaëlle Goubet, Máté Kiss, Béatrice Zitti, Thomas Zwahlen, Sheri Mcdowell, Ruben Bill, Simona Angerani, Camilla Engblom, Seth Anderson, Aiping Jiang, Oliver Hartley, David B. Sykes, Maja Jankovic, Nadine Fournier, Matthias Gunzer, David Tarussio, Stéphanie Tissot, Peter M. Sadow, William C. Faquin, Moshe Sade-Feldman, Ralph Weissleder, Sara Pai, François Mercier, Robert Manguso, Mikaël J. Pittet
Institutions: University of Geneva, Swiss Cancer Center Léman, University of Calgary, SIB Swiss Institute of Bioinformatics, University of Bern, University Hospital of Bern, Karolinska University Hospital, Science for Life Laboratory, Karolinska Institutet, Broad Institute, Harvard University, Massachusetts General Hospital, Massachusetts Institute of Technology, Mass General Brigham, Lady Davis Institute for Medical Research, McGill University, Essen University Hospital, Leibniz Institute for Analytical Sciences - ISAS, University of Duisburg-Essen, Centre Hospitalier Universitaire Vaudois, Center for Systems Biology, Yale University, University Hospital of Geneva, Ludwig Cancer Research
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: American Society of Hematology, Belgian American Educational Foundation, Ludwig Institute for Cancer Research, Human Frontier Science Program, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Hôpitaux Universitaires de Genève, Fondation ISREC, National Institutes of Health, Horizon 2020 Framework Programme, HORIZON EUROPE Marie Sklodowska-Curie Actions
Awards: G400242710, Tumor-infiltrating DC3s in the perivascular space – relevance for cancer immunity?, Targeting the tumor endothelium to sensitize lung cancer to immune checkpoint inhibition, Studying the modulation of CCR5 trafficking by chemokine analogues with potent anti-HIV activity, G6627423623, Molecular and Cellular Mechanisms Regulating Intratumoral DC3 Responses, G9000033010
OpenAlex ID: W7128081200