Neutrophils as active regulators of the immune system in the tumor microenvironment

In recent years, the role of immune cells in tumor progression has been a matter of increasing interest. Neutrophils constitute an important portion of the immune cells infiltrating the tumor microenvironment. Traditionally viewed as the first line of defense against infections, it is now well accepted that neutrophils also have an important role in multiple aspects of cancer biology. Multiple and heterogeneous neutrophil subsets have been identified in tumors and in circulation. Evidence from many studies now supports the notion that tumor-associated neutrophils (TANs) show functional plasticity driven by multiple factors present in the tumor microenvironment. In this review, we first concisely discuss the pro-tumor vs. anti-tumor nature of neutrophils in cancer, their functional plasticity, and the mechanisms that regulate neutrophil polarization. We then expand on the various crosstalks and mutual effects between TANs and other tumor-infiltrating immune cell types, emphasizing the active role of neutrophils as regulators of the immune system, promoting or inhibiting the establishment of a permissive tumor microenvironment. Finally, the possible modulation of cancer-related neutrophils by therapies directed toward immune checkpoints is discussed briefly.