Neutrophils: A Double-Edged Sword for Cancer Immunotherapy

High Resolution Image Download MS PowerPoint Slide Neutrophils represent one of the core effector cells composed of innate immunity that exhibits dynamic heterogeneity with a role of double-edged sword in the tumor microenvironment (TME). Tumor-derived cytokines polarize neutrophils into the anti-tumorigenic N1 tumor-associated neutrophils (TAN) and pro-tumorigenic N2 TAN phenotypes. The N1 TAN directly kills tumor cells and enhances adaptive immunity by releasing reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and immune regulatory molecules. However, the N2 TAN accelerates tumor progression by relying on NETs to construct premetastatic ecological niches, secreting pro-angiogenic factors, and shaping the immunosuppressive microenvironment. Neutrophils are key regulators of immune responses and play a pivotal role in tumor immune evasion. In innate immunity, they enhance nonspecific defenses by promoting the recruitment and activation of monocytes, macrophages, dendritic cells (DCs), and natural killer (NK) cells. In adaptive immunity, they facilitate the differentiation of monocytes and DCs into antigen-presenting cells (APCs), thereby augmenting the antigen-specific responses of T and B cells. However, compared to the extensively investigated macrophage polarization for innate immunity activation, neutrophil polarization in the TME remains less explored. This review provides a comprehensive analysis of neutrophil heterogeneity development within the tumor microenvironment and its dichotomous pro-tumorigenic versus anti-tumorigenic mechanisms. We specifically address emerging neutrophil-targeted drug delivery platforms and innovative approaches to reprogram neutrophil function for enhanced anti-tumor immunity. These insights establish a conceptual framework for advancing precision neutrophil-based therapeutics.