Neutrophils and their products are increasingly recognized to have a key influence on cancer progression and response to therapy. Their involvement has been shown in nearly every aspect of cancer pathophysiology with growing evidence now supporting their role in resistance to a variety of cancer therapies. Recently, the role of neutrophils in cancer progression and therapy resistance has been further complicated with the discovery of neutrophil extracellular traps (NETs). NETs are web-like structures of chromatin decorated with a variety of microbicidal proteins. They are released by neutrophils in a process called NETosis. NET-dependent mechanisms of cancer pathology are beginning to be appreciated, particularly with respect to tumor response to chemo-, immuno-, and radiation therapy.
Figure 1. Involvement of NETs in resistance to systemic and local cancer therapies. NETs are DNA webs extruded by neutrophils and associated with NE, MMP-9, CG, CEACAM1, and PD-L1 proteins, among others. These proteins are known to drive mechanisms associated with neoplastic resistance to systemic and local therapies. NETs may promote a microenvironment that favors the development of such a phenotype by sequestering tumor cells, bringing them into contact with these proteins, and driving multiple mechanisms of resistance concurrently. The functional role of NETs in resistance to chemo-, immuno-, and radiation therapy has been reported . Proposed mechanisms thereof include NETs coating neoplasms and preventing contact with cytotoxic immune cells, T-cell exhaustion through CEACAM1/TIM-3 interactions and the PD-1/PD-L1 axis, drug detoxification, angiogenesis through CG and MMP-9 activity, and NE-dependent EMT, among others. Created with BioRender.com (accessed on 28 January 2022).