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ResearchIn-Press PreviewCell biologyImmunologyOncology Open Access | 10.1172/JCI204067

Neutrophil-progenitor feedback sustains splenic myelopoiesis and promotes immune evasion in cancer

Lan Zhu,1 Shufeng Luo,2 Qiaomin Hua,3 Chang-An Zhao,1 Huiling Lin,3 Mingyu Liu,3 Lingyan Zhu,4 Jiabin Zheng,5 Huolun Feng,5 Yong Li,5 Chong Wu,1 and Limin Zheng1

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Zhu, L. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Luo, S. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Hua, Q. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Zhao, C. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Lin, H. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Liu, M. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Zhu, L. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Zheng, J. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Feng, H. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Li, Y. in: PubMed | Google Scholar

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Wu, C. in: PubMed | Google Scholar |

1School of Life Sciences, Sun Yat-sen University, Guangzhou, China

2Xiangya Cancer Center, Central South University, Guangzhou, China

3Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China

4School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

5Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

Find articles by Zheng, L. in: PubMed | Google Scholar |

Published October 6, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI204067.
Copyright © 2026, Zhu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 6, 2026 - Version history
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Abstract

Splenic myelopoiesis supplies immunosuppressive myeloid cells in cancer, yet its local regulation remains unclear. Here we identify a self-amplifying circuit between neutrophils and hematopoietic stem and progenitor cells (HSPCs) that sustains splenic myelopoiesis. Tumor-associated neutrophils produced reactive oxygen species (ROS) and created an oxidatively stressed milieu in the spleen, which activated FOXO1 in neighboring HSPCs and drove DRP1-mediated mitochondrial fission, reprogramming HSPCs toward myeloid-biased expansion and immunosuppressive output. Progeny neutrophils reinforced splenic oxidative stress and perpetuated this loop. Genetic ablation of Cybb or spleen-targeted ROS scavenging inhibited FOXO1 activation and preserved fused mitochondria morphology in HSPCs. Consistently, blockade of FOXO1 or DRP1 prevented mitochondrial fission and reduced ROS-producing myeloid cell generation. Such interventions reduced splenic myelopoiesis, curtailed the production of suppressive myeloid cells in the spleen and their infiltration into tumors, and enhanced cytotoxic T cell activity, thereby restoring antitumor immunity and restraining tumor progression. Analyses of spleen samples from cancer patients, together with cord-blood HSPC and neutrophil co-culture experiments, support the human relevance of this neutrophil–ROS–HSPC axis. These findings reveal a self-propagating neutrophil–HSPC feedback circuit that locally sustains tumor-promoting splenic myelopoiesis and provide a rationale for targeting neutrophil-to-progenitor signaling to normalize antitumor immunity.

Graphical Abstract
graphical abstract
Supplemental material

View Table S4 summarizes single-cell RNA-seq analyses of LSK cells from tumor-bearing mice, including cluster features, regulons, chromatin activity, and pseudotime-associated gene-set activity.

View Unedited blot and gel images

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Version history
  • Version 1 (October 6, 2026): In-Press Preview
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