Repositioning neutrophils in cancer immunotherapy: From innate defenders to antibody-driven effectors

Neutrophils, the most abundant innate immune cell population in human circulation, serve as frontline defenders through canonical mechanisms including degranulation, generation of reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation. Beyond their classical antimicrobial functions, emerging evidence positions neutrophils as critical effectors in antibody-based cancer immunotherapy. Through Fc receptor-mediated mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and trogocytosis, as well as strategies engaging the IgA-FcαRI (CD89) axis, neutrophils elicit enhanced antitumor responses compared to conventional IgG-based modalities. Building upon this framework, therapeutic approaches have progressed from granulocyte colony-stimulating factor (G-CSF)-mediated neutrophil expansion to bispecific antibody platforms that actively redirect neutrophils toward tumor cells, with proof-of-concept established in hematologic malignancies through CD89-targeting bispecific formats. However, in solid tumors, the immunosuppressive tumor microenvironment (TME) and skewing toward a protumorigenic N2 phenotype substantially hinder neutrophil-mediated cytotoxicity. To overcome these limitations, recent efforts have focused on reprogramming neutrophil functions through TGF-β blockade and rational immunotherapeutic combinations. Collectively, these integrative strategies offer the potential to reposition neutrophils from classical innate immune sentinels to dynamic effectors in antibody-based cancer immunotherapy.