Metastasis　is　the　leading　cause　of　cancer-related　death　and　a　critical　challenge　in　improving　cancer　treatment　today.　Circulating　tumor　cells　(CTCs)　adhesion　to　and　across　the　vascular　endothelium　are　critical　steps　in　the　establishment　of　micrometastatic　foci　away　from　the　primary　tumor.　Therefore,　we　believe　that　interrupting　CTCs　adhesion　to　endothelium　and　transendothelial　migration　may　efficiently　prevent　cancer　metastasis.　Fucoxanthin　(Fx)　is　an　algal　carotenoid　widely　distributed　in　brown　algae,　macroalgae,　and　diatoms.　Previous　studies　have　found　that　Fx　has　various　pharmacological　activities,　including　antidiabetic,　antioxidant,　anti-inflammatory,　anti-obesity,　antimalarial,　anticancer,　and　so　on.　However,　it　remains　unclear　whether　Fx　has　a　preventive　effect　on　cancer　metastasis.　Here,　we　found　that　Fx　interrupts　breast　cancer　cells　MCF-7　adhesion　to　endothelium　and　transendothelial　migration,　thus　inhibiting　CTCs-based　pulmonary　metastasis　in　vivo.　The　hetero-adhesion　assay　showed　that　Fx　significantly　inhibited　the　expression　of　inflammatory　factor-induced　cell　adhesion　molecules　(CAMs)　and　the　resulting　adhesion　between　MCF-7　cells　and　endothelial　cells.　The　wound-healing　and　transwell　assays　showed　that　Fx　significantly　inhibited　the　motility,　invasion,　and　transendothelial　migration　abilities　of　MCF-7　cells.　However,　the　same　concentration　of　Fx　did　not　significantly　alter　the　cell　viability,　cell　cycle,　apoptosis,　and　ROS　of　breast　cancer　cells,　thus　excluding　the　possibility　that　Fx　inhibits　MCF-7　cell　adhesion　and　transendothelial　migration　through　cytotoxicity.　Mechanistically,　Fx　inhibits　the　expression　of　CAMs　on　endothelial　cells　by　inhibiting　the　NF-кB　signaling　pathway　by　down-regulating　the　phosphorylation　level　of　IKK-α/β,　IкB-α,　and　NF-кB　p65.　Fx　inhibits　transendothelial　migration　of　MCF-7　cells　by　inhibiting　Epithelial-to-mesenchymal　transition　(EMT),　PI3K/AKT,　and　FAK/Paxillin　signaling　pathways.　Moreover,　we　demonstrated　that　Fx　significantly　inhibits　the　formation　of　lung　micrometastatic　foci　in　immunocompetent　syngeneic　mouse　breast　cancer　metastasis　models.　We　also　showed　that　Fx　enhances　antitumor　immune　responses　by　substantially　increasing　the　subsets　of　cytotoxic　T　lymphocytes　in　the　peripheral　immune　system.　This　new　finding　provides　a　basis　for　the　application　of　Fx　in　cancer　metastatic　chemoprevention　and　suggests　that　interruption　of　the　CTCs　adhesion　to　endothelium　and　transendothelial　migration　may　serve　as　a　new　avenue　for　cancer　metastatic　chemoprevention.　Copyright　©　2022　Wang,　Fu,　Lin,　Lu,　Lian,　Xie,　Zhou,　Li,　Zhang,　Jia,　Zhong　and　Huang.