Therapeutic potential of tumor-associated neutrophils: dual role and phenotypic plasticity

Neutrophils are the first line of defense in nonspecific immunity (innate immunity) and interact with other immune cells to participate in specific defense mechanisms (adaptive immunity). Studies have shown that the tumor microenvironment (TME) mediates tumor development and recruits neutrophils into tumors to become tumor-associated neutrophils (TANs), an important part of TME, and achieve extended lifespan. TANs can be differentiated into the antitumor or protumor phenotype, and play an important role in tumor occurrence, proliferation and recurrence, invasion and metastasis, angiogenesis, cell necrosis, and so on. Here, we summarize the TAN origin and subtypes found through Single-cell RNA sequencing analysis in different types of tumors in recent literature, and the molecular mechanisms underlying their antitumor and protumor effects on tumors. We focus on the interaction between TANs and immunosuppressive or immunostimulatory TME, as well as signal pathways such as transforming growth factor β (TGF-β) associated with TAN phenotype transition. Based on the summarized mechanisms, we focus on the potential application and latest strategies of TAN-based immunotherapy, chemotherapy, and combination therapy in the preclinical study and clinical trials of tumors. The discussion on promising therapy encompasses five key areas: inhibition of the tumor-promoting effect of TANs, enhancement of the antitumor effect of TANs, targeting the interaction between TANs and the TME, reprogramming of TANs, and drug delivery carriers. Finally, we discuss the potential of TANs and their related markers as emerging biomarkers for predicting the prognosis of cancer patients.