Peptide nano-blanket impedes fibroblasts activation and subsequent formation of pre-metastatic niche

Here we report an enzyme-activatable assembled peptide FR17 that can serve as a “flame-retarding blanket” at pre-metastatic niche (PMN) specifically to extinguish the “fire” of tumor-supportive microenvironment adaption. Our experiment demonstrated that the assembled peptide successfully reversed extracellular matrix deposition, vascular leakage and angiogenesis through inhibition on fibroblasts activation in PMN, which suppressed the remodeling of metastasis-supportive host stromal, and further prevented the recruitment of myeloid cells to PMN and then recovered the immunosuppressive microenvironment. Cell transcriptomic analysis of the pulmonary recruited MDSC suggested that FR17 intervention could regulate immune response activation, immune cells chemotaxis and migration pathways. Consequently, FR17 administration effectively inhibited pulmonary PMN formation and postoperative metastasis of melanoma, with only 30% lung-metastasis occurrence was observed for FR17 treated group at the time point when 100% occurrence was observed for the control group and 80% occurrence for anti-PD1 treated group, offering a robust therapeutic strategy against PMN establishing to prevent metastasis. A total of 4 samples were analyzed, including control (Ctrl), TP5, sFD17 and FR17. RNA preparations were extracted from CD11b+Ly6g+ myeloid-derived supperssor cells (MDSCs) sorted from lungs pooled from 10-12 mice from each group per sample.