Neutrophil polarization landscapes in HCC: From immunosuppressive niches to antitumor immunity resuscitation

Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality, arising predominantly in the context of chronic liver injury and cirrhosis. The tumor microenvironment (TME) is a critical orchestrator of HCC progression and therapeutic resistance. Neutrophils, the most abundant circulating leukocytes and key first responders in hepatic immunity, play a pivotal and multifaceted role in this process. Under physiological conditions, neutrophils are essential for liver homeostasis and acute injury resolution. However, across the pathological continuum from chronic liver disease to HCC, sustained inflammatory signaling drives a profound reprogramming of neutrophil function. Within the established HCC TME, tumor-associated neutrophils (TANs) are frequently polarized into a protumorigenic phenotype, actively driving disease progression through several core mechanisms: they establish immunosuppressive niches by directly suppressing cytotoxic T-cell function; promote angiogenesis and metastasis via the secretion of factors like VEGF and MMPs; and contribute to genomic instability and therapy resistance through mechanisms such as neutrophil extracellular trap (NET) formation. This functional transition from defenders in acute injury to accomplices in malignant progression underscores the central role of neutrophils in liver pathobiology and HCC pathogenesis. This review synthesizes current knowledge on the recruitment, polarization, and functional diversity of neutrophils in the HCC TME, with a particular focus on their mechanisms in mediating immunosuppression through cellular crosstalk and metabolic reprogramming. We further critically evaluate emerging therapeutic strategies that target neutrophil-centric pathways to resuscitate antitumor immunity, including TAN repolarization, depletion of specific subsets, or functional blockade. Finally, we discuss the translational potential of neutrophil-related biomarkers for patient stratification and the rationale for developing combination therapies. A deeper understanding of the dynamic and pleiotropic roles of neutrophils in HCC is essential for devising more effective immunotherapeutic strategies and improving patient outcomes.