Tumor Acidosis Boosts Antibody-Driven Cytotoxic Potential of Neutrophils

The acidic tumor microenvironment (pH 6.3-7.1) influences immune cell function, yet its impact on antibody-mediated killing remains poorly understood. While natural killer (NK) cells lose their spontaneous tumor-killing ability in acidic conditions, the effect on IgG-mediated killing is unexplored. Neutrophils, key effector cells in IgA immunotherapy, respond to pH changes by delayed apoptosis and show impaired bacterial killing. In this study, we investigated how extracellular acidity affects immune cell function and modulates antibody-dependent cytotoxicity by neutrophils and peripheral blood mononuclear cells (PBMCs) across multiple in vitro tumor models. Contrary to expectations, acidity significantly enhanced both IgG- and IgA-mediated tumor cell killing by neutrophils, while IgG-mediated antibody-dependent cellular cytotoxicity (ADCC) by PBMCs had a varying impact. This increased neutrophil activity was accompanied by elevated IgA-driven trogocytosis, while protumor reactive oxygen species production and neutrophil extracellular trap (NET) formation were suppressed. Cytokine profiling and Western blot analysis revealed increased Leukotriene B4 (LTB4) secretion and extracellular signal-regulated kinase (Erk) signaling, supporting enhanced neutrophil recruitment and activation in acidic conditions. Our findings reveal that, unlike other immune subsets, neutrophils maintain or even boost antibody-mediated effector functions in the acidic tumor microenvironment, providing new insight into neutrophil biology in tumors and supporting further investigation of neutrophil-targeted antibody immunotherapies.