Highly Selective Exogenous Neutrophils Effectively Inhibit Growth of Colon Cancer under the Guidance of Precision Navigation.

The diversity of neutrophils' subtypes and functions in the tumor microenvironmentunderlies their contributions to both pro- and anti-tumorigenic activities. How to elucidate the antitumor mechanisms of neutrophil and effectively utilize it still needs to be studied. In this study, neutrophil stimulus reaction index (NSRI) was established for high selectivity of neutrophils. Sufficient and highly selective exogenous neutrophils were used to infuse into tumor-bearing mice. Navigation technique was used to make neutrophils rapidly infiltrate into the tumor tissue, which played a key role in inhibiting tumor growth. We found that tumor cells were efficiently killed in direct coculture with sufficient neutrophils by promoting a multimodal death primarily dominated by apoptosis. Interestingly, colon cancer organoid diameters were decreased markedly cocultured with neutrophils, and were more remarkable in the application of organoid microinjection of neutrophils. Consistent with the 3D-printed model, in vivo model indicated that neutrophils meaningfully inhibited the tumor growth by formation of neutrophil extracellular traps (NETs) with neutrophil elastase (NE) payload. This study not only unveils the crucial anticancer effects of neutrophils but also sets out an innovative strategy of aggressive dose exogenous neutrophils with precise navigation, which provided the basis for advancements in neutrophil-based immunotherapy for colon cancer treatment.