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

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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.

Authors

Lan Zhu, Shufeng Luo, Qiaomin Hua, Chang-An Zhao, Huiling Lin, Mingyu Liu, Lingyan Zhu, Jiabin Zheng, Huolun Feng, Yong Li, Chong Wu, Limin Zheng