A　perfect　microenvironment　facilitates　the　activated　circulating　tumor　cells　(CTCs)　to　spark　the　adhesion-invasion-extravasation　metastatic　cascade　in　their　premetastatic　niche.　Platelet-CTC　interaction　contributes　to　the　progression　of　tumor　malignancy　by　protecting　CTCs　from　shear　stress　and　immunological　assault,　aiding　CTCs　entrapment　in　the　capillary　bed,　enabling　CTCs　to　successfully　exit　the　bloodstream　and　enter　the　tissue,　inducing　epithelial-mesenchymal-like　transition　(EMT),　and　assisting　in　the　establishment　of　metastatic　foci.　To　prevent　the　cascade　from　sparking,　we　show　that,　the　multifunctional　S-nitrosocaptopril　(CapNO)　acts　on　both　CTCs　and　platelets　to　interrupt　platelet/CTCs　interplay　and　adhesion　to　endothelium,　thus　inhibiting　CTC-based　pulmonary　metastasis　in　vivo.　The　activated　platelets　cloak　cancer　HT29　cells,　resulting　in　HT29-exhibiting　platelet　biomarkers　CD61　and　P-selectin　positive.　CapNO　inhibits　both　sialyl　Lewis(x)　(Slex)　expression　on　HT29　and　ADP-induced　activation　of　platelets　through　P-selectin-　and　GPIIb/IIIa-dependent　mechanisms,　confirmed　by　the　corresponding　antibody　assay.　CapNO　inhibits　platelet-　or　interleukin　(IL)-1　beta-mediated　adhesion　between　HT29　and　endothelial　cells,　and　micrometastatic　formation　in　the　lungs　of　immunocompetent　syngeneic　mouse　models.　CapNO　have　also　shown　the　effects　of　vasodilation,　anticoagulation,　inhibition　of　matrix　metalloproteinase-2　(MMP2)　expression　on　cancer　cells,　and　inhibition　of　cell　adhesion　molecules　(CAMs)　expression　on　vascular　endothelium.　Due　to　a　series　of　the　beneficial　effects　of　CapNO,　CTCs　remain　exposed　to　the　hostile　bloodstream　environment　and　are　vulnerable　to　death　induced　by　shear　stress　and　immune　elimination.　This　new　discovery　provides　a　basis　for　CapNO　used　for　cancer　metastatic　chemoprevention,　and　might　suggest　regulation　of　the　CTCs　bloodstream　microenvironment　as　a　new　avenue　for　cancer　metastatic　prevention.