In various types of malignant tumors, metastasis is responsible for most of the tumor-induced death. Though emerging technologies provided early detection of tumor metastasis or even warning of high metastatic risk before the actual occurrence of metastasis, clinical treatment on metastasis prevention lags far behind. Evidences have illustrated that primary tumor induced pre-metastatic niche (PMN) formation in distal organs by producing pro-metastasis factors, spreading the spark to ignite the distal microenvironment. Given the fundamental role of PMN in the development of metastases, interruption of PMN formation would be a promising strategy to take early actions against tumor metastasis. Here we report an enzyme-activatable assembled peptide FR17 that can serve as a “flame-retarding blanket” at PMN site 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.