OpinionReshapingtheImmuneTumorMicroenvironmentThroughIRE1SignalingCamilaRubio-Patiño,1JozefP.Bossowski,1EricChevet,2,3andJean-EhrlandRicci1,*Theabilityofatumorcelltocopewithenvironmentalandintracellularstressdependsonitscapacitytoactivateappropriateadaptivepathways.Assuch,theendoplasmicreticulum(ER)adjuststheadaptivecapacityoftumorcellsbyengagingtheunfoldedproteinresponse(UPR).TheUPRmaintainsthefunc-tionalityofthesecretorypathway,therebyallowingtumorcellstoshapetheirmicroenvironment,thuslikelydeterminingthenatureofthetumorimmuneresponse.Consequently,thismakestheUPRveryrelevantinthecontextofcancertherapeutics.Wefocushereoninositol-requiringenzyme1a(IRE1)andcompilenovelmolecularmechanismsdemonstratingthattumoralUPRcon-trolsthetumormicroenvironment(TME)andtheimmuneresponse,thereforeopeningpotentialnoveltherapeuticavenues.TheUPR:ControllingtheBrakeofCancerTheabilityofcancercellstorespondtoextrinsicandintrinsicstressdependsontheircapacitytosuccessfullyactivateappropriateadaptivepathways[1,2].Inthecourseofcarcinogenesis,intrinsic(e.g.,oncogene-drivenproteinsynthesis,reactiveoxygenspecies)orextrinsic(e.g.,hypoxia,nutrientshortage,chemotherapy)challengesimpingeoncellularproteinhomeostasis(proteostasis;seeGlossary)[3].Intheendoplasmicreticulum(ER),animbalanceinproteostasisleadstoasituationknownasERstress[2,4].TorestoreERproteostasisanadaptivesignalingpathway,theUPR,istriggered[3]thatismainlycontrolledbythreeER-residentsensors:IRE1,proteinkinaseRNA-likeendoplasmicreticulumkinase(PERK),andactivatingtranscriptionfactor6(ATF6)(Figure1andBox1).TheUPRattenuatesproteintranslation,enhancesproteinfoldingandqualitycontrol,andincreasesERclearancecapacity.Assuch,UPR-mediatedadaptationhasbeenproposedtocontributetocancerdevelopment[5].Thiswaslaterconfirmedinvariouscancersandwasfoundtoplayeitherprotumorigenic[6]orantitumorigenicroles[7,8].TheDualRoleoftheIRE1SignalinginCancerCellFate:LifeorDeathTheUPRcanaffecttumorcellbiologyeitherasabarriertotumordevelopmentorbypromotingestablishedtum...
