Agonist signaling drives neutrophil subpopulations to promote/inhibit colorectal cancer liver metastasis
Zhuoqing Xu, Haoran Feng, Wenqing Feng, Yuchen Zhang, Jianting Huo, Zifeng Xu, Fangqian Chen, Han Gao, Zeping Lv, Wangyi Liu, Abudumaimaitijiang Tuersun, Suyue Yu, Wenchang Li, Yaping Zong, Xiaohui Shen, Xi Cheng, Jingkun Zhao, Aiguo Lu
Abstract
Liver metastasis is a primary cause of death in colorectal cancer, yet the role of immune cells called neutrophils in this process remains complex. In this study, we identify three distinct neutrophil subtypes: anti-tumor high-density neutrophils, pro-tumor mature low-density neutrophils, and immature low-density neutrophils. Here we show that tumor-derived GM-CSF converts anti-tumor neutrophils into a pro-tumor state via the AKT–NF-κB–NFAT5 signaling axis. These activated neutrophils, when further stimulated by CXCR2 ligands, release web-like structures known as neutrophil extracellular traps which promote cancer spread by enhancing cancer cell growth, suppressing immune responses, and preparing the liver for metastasis. Importantly, we demonstrate that using antibodies depleting neutrophils or drugs inhibiting their pro-tumor activity effectively reduces liver metastasis in mice. Our work defines specific neutrophil subsets as key drivers of cancer progression and highlights their therapeutic potential in preventing metastatic spread. Liver metastasis remains a leading cause of colorectal cancer mortality. This study identifies different neutrophil subtypes involved in metastasis, highlighting therapeutic potential of neutrophil subset targeting to inhibit tumor progression.