Targeting S100A8/A9-NCF1 axis in tumor microenvironment to prevent tumor metastasis by self-assembled peptide nanofibers.

The immunosuppressive microenvironment plays a crucial role in driving and accelerating tumor metastasis. S100A8/A9, produced by myeloid-derived suppressor cells, is a potential therapeutic target for metastatic cancer due to its role in promoting premetastatic niche formation. Previous studies have revealed that the S100A9-targeted peptide (H6, MEWSLEKGYTIK) fused to the Fc region of mouse IgG2b antibodies exhibits antitumor effects; however, the mechanism remains unclear. Here, dual-function peptide nanofibers (H6-Q11) were constructed, consisting of peptide H6 and self-assembly peptide (Q11, QQKFQFQFEQQ), which achieved high avidity for S100A9. In vivo studies showed that H6-Q11 nanofibers significantly prolonged lung retention and inhibited pulmonary metastasis from melanoma and breast cancer without obvious toxicity. Immunological analyses indicated that treatment with H6-Q11 nanofibers decreased the infiltration of immunosuppressive cells while promoting the recruitment of immune effector cells to the lungs, potentially correlated with disturbances of S100A8/A9-NCF1 signaling in the tumor microenvironment. Our findings support a potential clinical application of S100A9-targeted peptide nanofibers as candidate nanomedicine for inhibiting tumor metastasis.