中性粒细胞胞外诱捕网的时空控制增强了中性粒细胞免疫疗法对实体瘤的疗效

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).