Heterogeneous neutrophils: Key players in regulating tumor immunity

As the most abundant innate immune cells in bone marrow and peripheral blood, neutrophils were once considered functionally homogeneous and exerted inflammatory and anti-infection functions. However, emerging evidence reshapes the perception of neutrophils from passive effectors to dynamic regulators with high plasticity and heterogeneity, especially within the tumor microenvironment (TME). This review summarizes recent advances, particularly driven by single-cell technologies, demonstrating that tumor-associated neutrophils (TANs) represent a continuum of distinct functional states originating from heterogeneous developmental pathways in bone marrow, circulation and spleen. We classified TANs into diverse subsets based on unique molecular signatures and functions, including pro-tumor, inflammatory, interferon-stimulated genes (ISGs)^high, and antigen-presenting subsets, and highlighted that TANs profoundly impacting tumor progression through distinct molecular mechanisms. Importantly, we delineate how TANs functionally interact with T cells, NK cells, macrophages and other immune cells, revealing the pivotal role of TANs in reconfiguring immune response networks to modulate tumor progression. Lastly, we discuss emerging therapeutic strategies targeting TAN recruitment, reprogramming, or specific pro-tumor subsets to overcome therapy resistance, aiming to provide insights for future research directions on neutrophils and the development of neutrophil-targeted cancer therapeutic strategies.