ReviewTurningColdintoHot:FiringuptheTumorMicroenvironmentQianqianDuan,1,2,5HualingZhang,3,5JunnianZheng,4,*andLianjunZhang1,2,*Cancersdevelopwithincomplextissueenvironmentsconsistingofdiversein-nateandadaptiveimmunecells,alongwithstromalcells,vascularnetworks,andmanyothercellularandnoncellularcomponents.Thehighheterogeneitywithinthetumormicroenvironment(TME)remainsakeyobstacleinunderstand-ingandtreatingcancer.Understandingthedynamicfunctionalinterplaywithinthisintricateecosystemwillprovideimportantinsightsintothedesignofeffec-tivecombinatorialstrategiesagainstcancer.Here,wepresentrecenttechnicaladvancestoexplorethecomplexityoftheTME.Then,wediscusshowinnateimmunesensingmachinery,geneticalterationsofoncogenicsignaling,cellularmetabolism,andepigeneticfactorsareinvolvedinmodulatingtheTME.Finally,wesummarizethepotentialstrategiestoboostantitumorimmunitybytherapeu-ticallyexploitingtheTME.ExploringtheTMEFormanydecades,effortshavebeenmadetoidentifythegeneticdrivermutationsofcancerinitiationandprogression.However,cancerprogressionisnotsolelydeterminedbygeneticalterationswithintumorcellsbutisalsocriticallyregulatedbythesurroundingniche,whichmayprovideimportantfac-torspromotingcancerdevelopmentorescapefromthesurveillanceofthehostimmunesystem[1].SinceRudolfVirchowobservedleukocytesinneoplastictissuesandfirstproposedthelinkbetweenchronicinflammationandtumorigenesis[2],acomprehensiveunderstandingofthetumormicroen-vironment(TME)(seeGlossary)ofsolidmalignanttissueshasattractedresearchers’attention[1].Infact,solidmalignanttumorscomprisenotonlytumorcellsbutalsovascularendothelialcells,fibroblastcells,andmanytypesofinnateandadaptiveimmunecells,togetherwithextracellularmatrix(ECM)aswellasmultipleextracellularsolublemolecules(cytokines,chemotacticfactor,growthfactors,etc.)[1].ImmunecellswithintheTMEcompriseimmunosuppressivecells,suchastumor-associatedmacro-phages(TAMs),myeloid-derivedsuppressorcells(MDSCs),andregulatoryT(Treg)cells,aswellastumor-fightingeffectorcells,suchascytotoxic...
