Spatiotemporal controls of neutrophil extracellular traps boosts neutrophils immunotherapy efficiency against solid tumors.

Abstract

Neutrophils have emerged as promising candidates for next-generation immunotherapies against solid tumors. However, the physical barrier formed by tumor-induced neutrophil extracellular traps (NETs) significantly restricts the migration and infiltration of circulating immune cells, thereby limiting their anti-tumor efficacy. This study demonstrated tumors driven NET formation. within recruited neutrophils via the Transforming Growth Factor Beta (TGFβ) signaling pathway. Therefore, a neutrophil-arming nanoplatform (NE@LTT@DNase1) was developed to enable neutrophils to degrade NETs while preserving their innate immune functions. Mechanistically, NE@LTT@DNase1 exerts dual therapeutic effects: (i) enzymatic degradation of pre-existing NETs via neutrophil surface-anchored DNase1 and (ii) spatiotemporal suppression of NETosis via endogenous lysine-trypotophan-threonine peptide (LTT) fragmentation in a reactive oxygen species-dependent manner. Data show that NE@LTT@DNase1 treatment was associated with increased infiltration of NK cells and T cells, as well as a shift of neutrophils and macrophages toward an anti-tumor polarization, collectively contributing to the reversal of the immunosuppressive tumor microenvironment (TME). In combination with anti-Programmed Death-1 (anti-PD-1) therapy, the NE@LTT@DNase1-based immunotherapy strategy resulted in a 74 % reduction in tumor burden and prolonged median survival by 61 % in tumor-bearing mice. Overall, these findings established a next-generation therapeutic paradigm for advanced neutrophil-based immunotherapy (NBI).