Biophysical reprogramming of immunosuppressive neutrophils by cold atmospheric plasma reinvigorates antitumor immunity

Neutrophils are increasingly recognized as key orchestrators of the immunosuppressive tumor microenvironment, yet their intrinsic plasticity, short lifespan and resistance to genetic manipulation have impeded therapeutic targeting. Here, we report a non-pharmacological, biophysical immunomodulatory strategy based on cold atmospheric plasma (CAP) to reprogram tumor-associated neutrophils and restore antitumor immunity. We show that CAP simultaneously delivers reactive oxygen species and redox cues that inhibit mitophagy, thereby restoring mitochondrial membrane potential and oxidative metabolism in neutrophils. This metabolic reinstatement drives a shift from immunosuppressive to immunostimulatory phenotypes. In both syngeneic and humanized bladder cancer models, intravesical CAP reshapes the myeloid landscape, enhances T cell infiltration, suppresses tumor progression, and sensitizes tumors to PD-1 blockade. These findings establish CAP as a locoregional, drug-free biophysical modality capable of overcoming neutrophil-mediated immune suppression and provide a materials-based framework for modulating innate immunity in solid tumors.