Rational targeting of immunosuppressive neutrophils in cancer

Neutrophils, the most abundant circulating leukocytes in human, play an indispensable role in the innate immune response to microbial infections. However, the contribution of tumor-associated neutrophils (TANs) to cancer progression and tumor immunity has been a matter of debate for decades. A higher neutrophil-to-lymphocyte ratio is associated with adverse overall survival in many solid tumors. Preclinical evidence exists to support both anti-tumor and pro-tumor activities of TANs, and TANs employ diverse mechanisms to influence tumor progression and metastasis. Here, we focus our review on the immunosuppressive mechanism of TANs and highlight how neutrophils can operate to dampen both innate and adaptive immunity to promote tumorigenesis. Here we discuss the intriguing and sometimes controversial connection between TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells (G/PMN-MDSCs). The molecular mechanisms underlying neutrophils' role in immunosuppression provide potential therapeutic targets for cancer treatment, either as monotherapies or as a part of combinatorial regimens. Therefore, we also highlight a number of neutrophil-targeting approaches that may improve the efficacy of current anticancer therapies, especially cancer immunotherapy. Currently interest is surging in the understanding and targeting of immunosuppressive neutrophils, with the goal of developing novel therapeutic strategies in the battle against cancer.