ReviewUbiquitinLigasesinCancerImmunotherapy–BalancingAntitumorandAutoimmunityYuFujita,1,4RobertoTinoco,2YanLi,1DanielaSenft,3andZe’evA.Ronai1,*ConsiderableprogresshasbeenmadeinunderstandingthecontributionofE3ubiquitinligasestohealthanddisease,includingthepathogenesisofimmu-nologicaldisorders.Ubiquitinligasesexertexquisitespatialandtemporalcontroloverproteinstabilityandfunction,andarethuscrucialfortheregulationofbothinnateandadaptiveimmunity.Giventhatimmuneresponsescanbebothdetrimental(autoimmunity)andbeneficial(antitumorimmunity),itisvitaltounderstandhowubiquitinligasesmaintainimmunologicalhomeostasis.Suchknowledgecouldrevealnovelmechanismsunderlyingimmuneregulationandidentifynewtherapeuticapproachestoenhanceantitumorimmunityandsafe-guardagainstautoimmunity.EmergingChallengesinCancerImmunotherapyFDAapprovalofimmunecheckpointblockers(ICBs)formelanomaandnon-smallcelllungcancer,andrecentlyforothermalignancies,isamajorbreakthroughincancertreatment[1,2].ICBsaremonoclonalantibodiesorantibody-basedmoleculesthatblockinhibitoryreceptorsortheirligands,mostnotablycytotoxicTlymphocyteantigen4(CTLA-4),programmedcelldeath1(PD-1),anditsligand,PDligand1(PD-L1).ThephysiologicalfunctionsofthesemoleculesincluderegulationofTcelldevelopmentandmaintenanceoftolerancetoself-antigens,processesthataredysregulatedinautoimmunedisorders[3,4].AlthoughblockingtheseproteinsdisinhibitsTcells,stimulatingtheirexpansionandeffectorfunctioninthetumormicroenvironment(TME),theactivationofautoreactiveTcells,whichcouldpromoteimmune-relatedadverseevents(IRAEs)oftenseenwiththesetherapies(Box1)remainsamajorcomplication[5].Themainchallenge,however,remainshowtoincreaseclinicalefficacyacrosstumor(sub)typesinmorepatients.Currently,combinedICBtreatmentsorregimensthatengageneoadjuvant,low-dosechemotherapiesorradiationtherapyhavebeendesignedtoaddressthislimitation;however,inmostcasestheriskofIRAEsremainsaconcern[2,5–7].Paradoxically,becauseIRAEsalsoserveasindicatorsforimmuneactivation[5],butcanoftenbetreatedwit...
