Heterogeneity of tumor-associated neutrophils in hepatocellular carcinoma

Neutrophils are the most abundant cell type in human blood and play a crucial role in the immune system and development of tumors. This review begins with the generation and development of neutrophils, traces their release from the bone marrow into the bloodstream, and finally discusses their role in the hepatocellular carcinoma (HCC) microenvironment. It elaborates in detail the mechanisms by which tumor-associated neutrophils (TANs) exert antitumor or protumor effects under the influence of various mediators in the tumor microenvironment. Neutrophils can exert antitumor effects through direct cytotoxic action. However, they can also accelerate the formation and progression of HCC by being recruited and infiltrated, promoting tumor angiogenesis, and maintaining an immunosuppressive microenvironment. Therefore, based on the heterogeneity and plasticity of neutrophils in tumor development, this review summarizes the current immunotherapies targeting TANs, discusses potential opportunities and challenges, and provides new insights into exploring more promising strategies for treating HCC. • The increase in low-density neutrophils and circulating neutrophils correlates with poor prognosis in HCC, underscoring their importance in research. • In HCC, neutrophil subpopulations' dynamic ratios and activities dictate their anti-tumor or pro-tumor roles. • Treating HCC with neutrophils involves targeting recruitment, blocking pathways, modulating phenotypes, and combined monoclonal antibody therapies. • Oncolytic viruses can transform the tumor microenvironment from "cold" to "hot," reverse immune cell suppression, and reduce tumor load. • Single-cell sequencing revealed the heterogeneity of TANs, and future work is expected to explore more effective and safe therapeutic strategies for HCC by specifically labeling TANs.