Neutrophils are the most abundant leukocyte in solid tumours, yet the programmes that generate tumour-supportive neutrophils remain poorly defined. The prevailing view holds that these cells acquire pro-tumour properties through local plasticity, and therapies built on this premise compromise bactericidal defence. We built the most comprehensive single-cell atlas of the neutrophil compartment assembled to date to resolve the functional architecture of granulopoiesis across health, aging, and disease. This atlas uncovered a distinct, non-canonical immunomodulatory neutrophil lineage (imNeutros) that does not arise from reprogramming of mature cells, but from a separate myelopoietic programme rooted in the bone marrow and expanded in lung cancer. imNeutros retain neutrophil morphology yet behave unlike any canonical neutrophil, showing a markedly extended lifespan, increased mitochondrial and lipid metabolism, poor chemotaxis, but with powerful antigen presentation properties. Our work shows that a granulopoietic switch, rather than the tumour-resident cell, can represent the actionable target in lung cancer, one that can be selectively dismantled without disarming antibacterial immunity.

Dr. Cerezo-Wallis is an Associate Research Scientist in the laboratory of Dr. Andrés Hidalgo at Yale University. She earned her doctorate under Dr. María S. Soengas at the Spanish National Cancer Research Centre (CNIO) in Madrid, where she worked on intrinsic mechanisms of melanoma metastasis and immunotherapy resistance via the reprogramming of tumor-associated macrophages. After her PhD, she earned a Cancer Research Institute fellowship and joined Dr. Andrés Hidalgo Lab, at the Spanish National Cardiovascular Disease Centre (CNIC) in Madrid, which later moved to Yale University. In her postdoctoral research, Daniela has focused on neutrophil biology. She generated the NeuMap, the most comprehensive map of neutrophil heterogeneity in health and disease produced to date, and identified a novel immunoregulatory neutrophil subset with key roles in anti-tumor immunity. Her recent work defines the deterministic principles by which tumors reprogram neutrophil development and function.