Figure 1. Pro-tumour mechanisms of tumour-associated neutrophils.

Direct effects of neutrophils on cancer cells: Neutrophils release a plethora of bioactive molecules that drive cancer development. Neutrophils secrete reactive oxygen species (ROS) which, through DNA damage, can drive malignant transformation of hepatocytes. They also secrete prostaglandin E₂ (PGE₂) and neutrophil elastase (NE), which can induce tumour cell proliferation; as well as matrix metalloproteinase 9 (MMP9), which promotes angiogenesis and extracellular matrix (ECM) remodelling in the tumour. Furthermore, release of neutrophil extracellular traps (NETs) promotes metastatic seeding of tumour cells in distal organs. Tumour cells express CD47 which, when bound to its ligand, signal regulatory protein α (SIRPα) found on the surface of neutrophils, impairs their phagocytic capacity; a process commonly known as the ‘do not eat me’ signal. A proportion of tumour cells also express the programmed death-ligand 1 (PD-L1) which, in contact with programmed cell death protein 1 (PD-1) in the surface of CD8⁺ T cells and granulocyte–monocyte progenitors (GMPs), suppresses their anti-tumour functions. Effects of neutrophils on the immune system: Neutrophils emit ROS, arginase 1 (ARG1) and nitric oxide (NO), which can immunosuppress cytotoxic CD8⁺ T cells. Moreover, cancer-associated fibroblasts (CAFs) secrete interleukin 6 (IL-6) that is recognised by JAK2-coupled chemokine receptors on the surface of neutrophils, also immunosuppressing T cells. Finally, neutrophils express PD-L1, V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) and CD86 which, in contact with their respective receptors/ligands on CD8⁺ T cells, can impair their cytotoxic ability. Figure created with BioRender.com