SpotlightFightingResilientCancerswithIronJonathanJ.Chen1andLorenzoGalluzzi1,2,3,*Tumorprogressionandresistancetotreatmentareoftenaccompa-niedbythepolarizationofmalig-nantcellstowardsamesenchymalorpoorlydifferentiatedstate.Suchatransitiongeneratesanaccruedvulnerabilitytotheinductionoffer-roptosis,potentiallypavingthewaytonoveltherapeuticstrategiesfortargetingresidualdiseaseinpatientswithcancer.Alargenumberofcell-intrinsicandcell-extrinsicmechanisms,includingautoph-agy,cellularsenescence,regulatedcelldeath(RCD),andimmunosurveillance,isinplacetopreventmalignanttransfor-mationorinterceptneoplasticcellprecur-sorsastheyform,hencemediatingrobustoncosuppressivefunctions[1,2].However,newlyformedmalignantcellscanoccasionallyescapethesesafe-guardsandbegintoproliferateastheyacquireconsistentphenotypic,meta-bolic,andimmunologicaldiversityandpolarizetowardsamesenchymalorpoorlydifferentiatedstate[3].Suchan‘epithelial-to-mesenchymal’transition(EMT)notonlyenablesthemultisteppro-cessleadingtothecolonizationofdistantanatomicalsites(theso-called‘meta-staticcascade’),butalsoendowsmalig-nantcellswithanaccruedresistancetoavarietyoftherapeuticregimens[4].Thus,tumorprogressionandacquiredresis-tancetotreatment,whichareultimatelyresponsibleformostcancer-relateddeaths,areintimatelyconnectedwiththereprogrammingofmalignantcellstowardsamesenchymalstate(Figure1).Inlinewiththisnotion,theEMThasattractedconsiderableattentionasapotentiallydruggableprocessforcancertherapy[4].Recentdatademonstratethatcancercellsexistinginsuchahighlymesenchymalstateexhibitanexquisitesensitivitytotheinhibitionofglutathioneperoxidase4(GPX4)[5,6],potentiallypavingthewaytonoveltherapeuticstrategiesforovercomingresidualdiseaseinpatientswithcancer.GPX4isaselenocysteine-containingenzymethatcatalyzestheglutathione-dependentreductionofspecificlipidhydroperoxidesintolipidalcohols[7].Byvirtueofthiscatalyticactivity,GPX4robustlyinhibitsferroptosis,aniron-dependent,lipidperoxide-drivenformofRCDthatisinvolvedinmultiplepatholog-...
