Theregulationofredoxhomeostasisisfundamentaltomaintainingnormalcellularfunctionsandensuringcellsurvival.Cancercellsarecharacterizedbyincreasedaerobicglycolysis(termedtheWarburgeffect)andhighlevelsofoxidativestress1.Thisoxidativestressisexertedbyreactiveoxygenspecies(ROS)thataccumulateasaresultofanimbalancebetweenROSgenerationandelimination.ThehighROSlevelsincancercellsareaconsequenceofalterationsinseveralsignallingpath-waysthataffectcellularmetabolism.TheseROSlevelsarecounteractedbyelevatedantioxidantdefencemecha-nismsincancercells2.Formanyyears,researchershavetheorizedthatcan-cercellsdependontheactivationofanoncogeneortheinactivationofatumoursuppressorgenefortheirsur-vival—ahypothesisknownas‘oncogeneaddiction’3.Basedontheideathatoncogenesandtumoursuppressorgenesareacriticalforceinthemalignanttransforma-tionofcells,pharmaceuticalcompanieshavefocusedondevelopingdrugsthattargetthesegenes.However,recentstudieshaveshedlightonthevitalmechanismsthatensurethesurvivalofcancercells,includingtheabilitytoescapefromimmunesurveillanceaswellastheabilitytocopewithaneuploidyandtoundergometabolicadaptationsthatprovidecancercellswithasecureenergysupplyandformadefencemechanismagainstvariouscellularstresses4.Thus,targetingthe‘cart’(immunesurveillance,aneuploidyandmetabolism)ratherthanthe‘horse’(oncogenesandtumoursuppres-sorgenes)maybeapromisingstrategyforeliminatingcancercellswhilesparingnormalcells.Inthecontextofcellmetabolism,itisnowapparentthatcancercellsadapttotheimbalancedredoxstatuscreatedbytheirrapidgrowthandotherconditions,suchasoxygenandlimitedavailabilityofnutrients,bydevel-opingalternativemetabolicreactionsthatrendertheminsensitivetofurtherstressinducerssuchaschemo-therapyandradiation5.Here,wediscussthecellularsensorsandmodulatorsofoxidativestress,andcon-siderhowadeepunderstandingoftheirfunctioncaninformthedevelopmentofanewtherapeuticstrategyagainstcancer.DefiningthebasisofoxidativestressROSarebroadlydefinedasoxygen-containingchemicalspecieswithreactiveproperties.T...
