Integrating　Fenton　chemistry　and　nanomedicine　into　cancer　therapy　has　significantly　promoted　the　development　of　chemodynamic　therapy　(CDT).　Nanoscale　polyoxometalates　(POMs),　with　their　reversible　redox　properties,　exhibit　promising　potential　in　developing　outstanding　CDT　drugs　by　exploring　their　Fenton-like　catalytic　reactivity　in　tumor　environments.　However,　such　research　is　still　in　its　infancy　due　to　the　challenges　of　acquiring　POMs　that　are　both　easily　prepared　and　possess　ideal　therapeutic　effects,　physiological　solubility,　biocompatibility　and　safety.　In　this　work,　we　report　the　synthesis　of　a　new　crystalline　antimonotungstate　{Dy2Sb2W7O23(OH)(DMF)2(SbW9O33)2}　(1,　DMF=N,　N-dimethylformamide)　with　gram-scale　high　yield　via　a　facile　“one-pot”　solvothermal　reaction.　1　exhibits　not　only　a　soluble　and　water-stable　POM　nanocluster,　but　also　excellent　catalytic　activity　for　hydroxyl　radical-generating　Fenton-like　reactions.　Further　biomedical　studies　reveal　that　1　can　trigger　cell　apoptosis　and　promote　lipid　peroxidation,　exhibiting　high　cytotoxicity　and　selectivity　towards　B16-F10　mouse　melanoma　cancer　cells　with　an　IC50　value　of　4.75　μM.　Especially,　1　can　inhibit　melanoma　growth　in　vivo　with　favorable　biosafety,　achieving　a　5.2-fold　reduction　in　tumor　volume　and　a　weight　loss　of　76.0　%　at　the　dose　of　70　μg/kg.　This　research　not　only　demonstrates　the　immense　potential　of　antimonotungstates　in　CDT　drug　development　for　the　first　time　but　also　provides　new　insights　and　directions　for　the　development　of　novel　anticancer　drugs.　©　2024　Wiley-VCH　GmbH.