Inhibiting NeutrophilExtracellular Trap Formationthrough Iron Regulation for Enhanced Cancer Immunotherapy

Iron metabolism of neutrophils plays a vital role in neutrophil extracellular trap (NET) formation, which presents as one of the major hurdles to the immune response in the tumor microenvironment. Here, we developed a peptide–drug conjugate (PDC)-based transformable iron nanochelator (TIN) equipped with the ability to regulate the iron metabolism of neutrophils, endowing inhibition of NET formation and the ensuing immunosuppression functions. The TIN could expose the iron-binding motifs through neutrophil elastase-mediated morphological transformation from nanoparticles to β-sheet nanofibers, which further evolve into stable α-helix nanofibers after chelation with iron(II) ions. This process enables a highly specific regulation of iron(II) ions of neutrophils, which turns into an efficient way of inhibiting NET formation and improving the immune response. Furthermore, the TIN showed an improved therapeutic effect in combination with protein arginine deiminase 4 inhibitors and synergistically boosted the anti-PD-L1 treatment. This study designates an iron-regulation strategy to inhibit NET formation, which provides an alternative approach to immune modulation from the perspective of targeting the iron metabolism of neutrophils in cancer immunotherapy.