REVIEWARTICLE

Anaplastic thyroid cancer: Genetic roles, targeted therapy, and immunotherapy

Zhao Zou ?, Linhong Zhong b,\*

aDivision of Cardiology,The First Affiliated Hospital of Chongqing Medical University, Chongqing
400010,China
ChongqingeyLaboratoryofUtrasoundMoleculrmaging,InstituteofUtrasoundImagingnd
DepartmentofUtrasoundTheSecondAffliated HospitalofChongqingMedicalUniversityChongqing
400010,China

Received 24 February 2024;received in revised form 2 July 2024;accepted 2August 2024
Availableonline30August2024

KEYWORDS

Anaplastic thyroid cancer;
ATC;
Genetic roles;
Immunotherapy; Targeted therapy

AbstractAnaplastic thyroid cancer(ATC)stands as themost formidableform of thyroid malignancy,presenting a persistent challenge in clinical management.Recent yearshave witnessed a gradual unveiling of the intricate genetic underpinnings governing ATC through next-generation sequencing.The emergence of this genetic landscape has paved the way for the exploration of targeted therapies and immunotherapies inclinical trials.Despite these strides,the precise mechanisms governing ATC pathogenesis and the identification of efficacious treatments demandfurtherinvestigation.Our comprehensive review stemsfrom an extensive literature searchfocusing onthe geneticimplications,notably the pivotal MAPK and PI3K-AKT-mTOR signaling pathways,along with targeted therapies and immunotherapies in ATC.Moreover,we screen and summarize the advances and challenges inthe current diagnostic approachesforATC,including theinvasive tissue sampling represented byfine needle aspiration and core needle biopsy,immunohistochemistry, and ^{18}\mathsf{F} -fluorodeoxyglucose positron emission tomography/computed tomography.We alsoinvestigate enormous studies on the prognosis of ATC and outline independent prognostic factors for future clinical assessment and therapyforATC.By synthesizing this literature,we aimto encapsulate the evolving landscape of ATC oncology,potentially shedding light on novel pathogenic mechanisms and avenues for therapeutic exploration.

⊚ 2024 The Authors.Publishing services by Elsevier B.V.on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Introduction

The incidence of thyroid cancer(TC)has experienced a global surge over the past five decades.Up to 2020,TC is theninthmostprevalentcancer worldwide.²Theglobal age-standardizedincidencerateinwomen(10.1per 100,000 women) is 3-fold than that in men (3.1 per 100,000 men),while both sexes share a similar global age-standardizedmortalityrate(0.3per100,000menand0.5per 100,000 women, respectively).2,3 Among thyroid malignancies,anaplastic TC (ATC), characterized as the most aggressive form，represents approximately 1.3%{-9.8%} of cases.4 Despite its clinical significance，the underlying mechanisms orchestrating ATC pathogenesis remain enigmatic.

Genetic alterationsplay apivotalroleinthepathogenesis of ATC.Notably, copy-number aberrations and singlenucleotide variants inATCs surpass thoseobservedin papillarythyroid cancer(PTC)but arefewercomparedwith mostother adultcancer types.Patientsexhibitinga lower mutationrate _{1>10} single-nucleotide variants per megabase)demonstratedsignificantlyimprovedsurvival(hazard ratio/H \mathsf{I R}=0.51 .， 95% confidence interval/Cl: 0.33-0.77; {±b P}=0.002 .5 Common genomic features shared between ATC and differentiated thyroid cancer(DTC)alsosuggest a common evolutionary origin.5During the anaplastic transformation of DTC, four distinct types of ATC cells emerge, including stress-responsive DTC cells,inflammatory ATC cells,mitotic-defectiveATCcells,and mesenchymalATC cells.6 Crucially, two stages are identified in this transformation，the diploid stage,characterized by inflammatoryATCcellsexhibitingdiploidgenomes andinflammatory phenotypes,and the subsequent aneuploid stage,marked by theacquisitionof aneuploidgenomes andmesenchymal phenotypes by mesenchymal ATC cells.6

Recently,advancements inhigh-throughput sequencing haveunveiled significant genetic alterations linked toATC's development(detailed inTable 1),providing pivotal insights intopotential target therapies alignedwith these geneticaberrations.Thesegeneticcues have sparked aray of hope for ATC patients， offering prospects for novel targettherapiesandimmunotherapies.

In this review,we aim to explore these genetic pointers and their relevance to emerging target therapies and immunotherapies in the context of ATC.

MAPK signaling pathway

Activationandfunction

Receptortyrosinekinases(RTKs)，integralsingle-span transmembranereceptors,encompass adiversespectrum organizedinto19distinctfamilies.Notable among these are epidermal growth factor receptor (EGFR),plateletderived growth factor receptor (PDGFR)，vascular endothelial growth factor receptor (VEGFR)，and fibroblast growthfactor receptor(FGFR).7Each RTKfamily binds to specific extracellular ligands,_ initiating intracellular signaling cascades upon binding.7

Uponactivation,RTKsoperateupstreamofratsarcoma (RAS), a small GTPase comprising three gene isoforms: HRAS, NRAS, and KRAS.8 RAS proteins directly engage phosphatidylinositol 3-kinase (Pl3K)，catalyzing the conversion of phosphatidylinositol 4,5-biphosphate (\mathsf{P l}\mathsf{P}_{2}) into phosphatidylinositol 3,4,5-trisphosphate (\mathsf{P l}\mathsf{P}_{3}) .9Consequently,RAS exerts itsinfluence upstream inboth the MAPK and PI3K-AKT signaling pathways.

ActivatedRAsinterfaceswithrapidlyaccelerated fibrosarcoma (RAF)，encompassing three isoforms: raf-1 proto-oncogene，serine/threonine kinase (CRAF)，v-raf murine sarcomaviral oncogenehomolog B1(BRAF),and araf proto-oncogene,serine/threoninekinase (ARAF).1°RAF heterodimerizes withMAPKkinase (MEK)，and active MEK phosphorylatesextracellularsignal-regulatedkinase (ERK).10 Subsequently, ERK travels to the nucleus, modulatingvarioustranscriptionfactors throughphosphorylation.11This MAPK signaling pathway is typically associated with cellular proliferation and survival mechanisms.12

RoleofMAPKsignalingpathwayinATC

RAS

RAS mutations manifest as a prevalent occurrence in ATC. These mutations span across all RAS isoforms,& with NRAS mutationsexhibiting ahigher incidence amongpatients younger than 50 years.13 Notably, RAS mutations are less frequentinsecondaryATCcomparedwithprimarycases and arefrequently linked to unfavorable prognoses.14Cases displayingBRAForRASmutationsdemonstratesimilarfrequencies in nodal and distant metastases.15,16 Of significance, K R A S^{\mathsf{G12D}} ，in conjunction with thyroid hormone receptor beta (THRβ)，orchestrates myc up-regulation, hastening ATC progression.17 Patients harboring wild-type KRAScodon12/13exhibiteda medianoverall survival (mOS) of 19 weeks.18

DistinctassociationssurfacebetweenRASmutations and othergenealterations.Forinstance,a mutualexclusivityis observed between B R A F^{\mathsf{v600E}} and RAS alterations.13 Moreover,RASmutations and tumorsuppressorgene p53(TP53) mutationsdominateandexhibitmutualexclusivityinATC and poorly differentiated thyroid cancer (PDTC).19Additionally,a gradually emerging correlation between eukaryoticinitiationfactorIAX(EIFIAX)mutationsandRAS in ATC is evident. EIF1AX mutations frequently_co-occur with RAS mutations in 117 PDTC and ATC cases.20 Notably, within a cohort of 31 patients，all three cases exhibiting combinations of severalgenetic mutations(EIF1AX，RAS, TERT, and TP53) were diagnosed as ATC.21

Proposalshaveemergedforastandardizedclassification ofATCbasedonRASandothermolecularbiomarkers.This includes delineating type 1 ATC (BRAF-positive)， likely originating from PTC; type 2 ATC (NRAS-positive), potentially originatingfrom follicular thyroid cancer(FTC);type 3 ATC (mutated RAS-positive), potentially originating from FTC or Huirthle cell carcinoma; and a mixed ATC subtype characterized by inactive mutations in cell-cycleregulation genes(e.g.,CDKN2A and CDKN2B).22

RAF (BRAF,BRAFV600E)

The role of BRAF mutation, particularly BRAFV600E, emerges as pivotal in ATC pathogenesis.Encoded by the BRAFT1799A mutation,23 BRAFV600E\* drivesheightenedextracellular signal-regulatedkinase phosphorylation,fostering aberrant cellproliferation andstiflingtheessentialgenes crucialfor radioiodine responsiveness in Tc.24 B-cell lymphoma-2- associated athanogene 3(BAG3）interaction with BRAF prevents proteasome-mediated degradation，sustaining ATC cell growth.25 Notably, in vivo experiments demonstrated that silencing BRAF inhibited tumor growth.26 Outcomeswerenotablyworseincases displayingconcomitant BRAF/RAS andTERT mutationscompared withsingular mutations,15 5withBRAF mutations exhibitinggreater prevalence in secondary ATC.14 Consequently, BRAF status assessmentbecameastapleinATCevaluations，with immunohistochemical detection showcasing 100% sensitivity and 95.7% specificity for B R A F^{\mathsf{V}600E} status in ATC.27 Additionally,reports indicate the utility of droplet digital PCR, based on fine needle aspiration (FNA),for rapid BRAFV600 detection in unresectable ATC.28

BRAFV600E significantly accelerates ATC progression, orchestratingcellularlactylationto_promoteproliferation.29 It collaborates with P1K3C A^{H1074R} (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is one ofPI3K catalytic subunits) or silences PTEN to advance ATC pathogenesis.30 Moreover, it impedes mitochondrialpermeability transition through thepERKpGSK-CypDpathway,thwarting ATC cell death.31Activation of the JAK/STAT pathway in B R A F^{\mathsf{V}600E} ATC cells contributes toresistanceagainst BRAF inhibitors.32 Knockdownof S100A4, overexpressed in ATC, led to reduced BRAFV600E expression，curbing proliferation and metastasis.33 Interestingly, B R A F^{~600E} correlates with cell-free DNA markers ALU83 and ALU244,associated with increased methylation, albeitdetectedlessfrequentlyinTCthaninPTC4linking BRAFV600E to oncogenic hypermethylation.35

Additionally，BRAF-mutatedATCdemonstratesarobust association with PTC.Evidence suggests both BRAF-positive PDTC and ATC harbor regions of preexisting papillary carcinoma，affirming BRAFmutationsinwell-differentiated and dedifferentiated components.36Thepresence ofBRAF mutationcldingFV00isbservedinTcoistin with PTC.37-40 Notably, cases of BRAF mutation were identified in ATCs derived from BRAF-mutant PTCs,41 underscoringthe engagement ofBRAF mutation,particularly BRAFV6o0E in the tumorigenesis of both ATC and PTC.

PI3K-AKT-mTOR signaling pathway

Activationandfunction

Theintertwinedsignalingpathways ofPI3K-AKT and the mechanistic target ofrapamycin(mTOR) stand as pivotal regulatorsorchestratingcellgrowthandsurvivalwithina unifiedsignalaxis.42Pl3Kcatalyzes theconversionfrom \mathsf{P l P}_{2} to {\mathsf{P I P}}_{3} ，where {\mathsf{P I P}}_{3} recruits proteinkinaseB(AKT）to the cellular membrane.43 AKT, in turn, governs cell survival andproliferationwhileexertingapositiveregulatoryeffect on mTOR.43 mTOR elevation contributes to increased levels of tumorigenesis-associated proteins like hypoxia-inducible factor44 and cyclin D1.45 Active AKT demonstrates heightenednucleardistributionandexpressionlevelsinbothATC andPTC.AKTdeficiency correlateswith diminished cellular proliferation andinvasivepotential,underscoringitsrole in disease progression.46 Notably, PTEN, a pivotal downstream effector of the PI3K-AKT-mTOR pathway，functions as a proteinandlipidphosphatase.Itsroleinvolvesthe dephosphorylation of {\mathsf{P l P}}_{3} into {\mathsf{P}}|{\mathsf{P}}_{2} 47thereby inhibiting the PI3K-AKT-mTOR cascade.By modulating {\mathsf{P l P}}_{3} levels,PTEN intricatelyregulates cell survival,proliferation，and migration.48 Moreover, the PI3K-AKT pathway potentially operatesdownstreamofthecentrosomalproteinof 55~\mathsf{k D a} (CEP55),an independent prognostic indicatorin ATC.49 This suggestsaregulatoryrelationshipbetweenCEP55andthe PI3K-AKT pathway, further emphasizing the intricate interplayofmolecularmechanismsinfluencingATCprogression and prognosis.

RoleofPI3K-AKT-mTORsignalingpathwayinATC

PrevalenceofmutationsinATC

Mutations within the PI3K-AKT-mTOR signaling pathway emergeasfrequentlyobservedinATC.Notably,mutations in PIK3CA，AKT， and PTEN are more prevalent in ATC compared with FTC.5° In a subset of PIK3CA-mutant ATC cases，activationof AKT wasevident in9out of 16instances.51 within a cohort of {50}\mathsf{A T C} cases, rates of PIK3CA copygain,PIK3CA mutations,and PTEN mutations stood at 42% ， 12% ,and 16% ,respectively.52The concurrent presence of BRAF and PIK3CA mutations in ATC was reported at a rate of 10.3% 53 both identified as adverse prognostic factors for ATC patient survival.54 Notably, patients exhibiting a PIK3CA mutation detected in circulating cell-free DNA showcased poorer overall survival(Os).55 Recent findings revealed a novel mTORpoint mutation(A1256G,exon 9) identified in the C643 ATC cell line.56 Moreover, a comprehensiveevaluationacross14ATCcasesunveileda complete loss ofPTEN mRNA expression in 4 instances, correlating significantly with the anaplastic subtype.57 TranscriptionalsilencingofPTENemergesasa noteworthy association within the context of ATCpathology，emphasizing its potential role in disease progression and subtype delineation.

Development of ATC

Themigration and invasion of ATC cells exhibit strong correlationswiththestatusofthePI3K-AKT-mTORpathway.OGlcNAcylation significantly augments ATC cell invasion, partly attributed toPI3K-AKTsignaling.58MicroRNA-125b exertsinhibitory effects ontumormigrationand invasionby targetingphosphoinositide3-kinasecatalyticsubunitdelta (PIK3CD),an alternate PI3K catalytic subunit.59within the intricate network，the Pl3K-AKT pathway interconnects withvariousaxesinfluencingATCaggressiveness.For instance,theHOXD9-MicroRNA-451a-PSMB8axismodulates apoptosis，promotes epithelial-mesenchymal transition, andexacerbatesmetastasiswithinATC,allorchestratedvia the PI3K-AKT signaling cascade.60 Vascular cell adhesion molecule-1(vCAM-1) contributestomigration and invasion through thePI3K-AKT-mTORpathwayin vitro，withboth VCAM-1and thepathway showing activationinBRAF-inhibition treatmentresistance.61Moreover,SrY-related HMG box-2(SOX2）intensifies ATC aggressiveness via PI3K-AKTmediated fibronectin 1 (FN1) up-regulation.62 The insulinlike growthfactor(IGF)produced by M2-like tumor-associatedmacrophages(TAMs)augmentsATCstemnessandinvasionbyactivating theIR-A/IGF1R-mediatedPI3K-AKTmTOR pathway.63 Intriguingly， grb2-associated binder 1 (GAB1）up-regulation stimulates AKT activation,cellular migration,and invasion throughAKT-MDR1,64while GANT61 suppressesinvasionandepithelial-mesenchymaltransition by targetingAKT-mTOR or JAK-STAT3 pathways inATC.65Akinase interacting protein 1 (AKIP1） knockdown inhibits PI3K-AKT and \upbeta -catenin pathways,mitigating cell invasion and reinstating sensitivity to doxorubicin (Dox).66 These multifacetedinteractionsunderscoretheintricateroleof thePI3K-AKT-mTORpathwayindictatingATCaggressivenessandtherapeuticresponses.

Resistance to agents

ThePI3K-AKT-mTOR pathway significantly contributes to chemotherapyresistanceinATC.Strategies targeting this pathway have shownpromise in overcoming resistance mechanisms.Lexatumumab，acting as a TNF-related apoptosis-inducing ligand receptor 2(TRAIL-R2） agonist antibody,effectivelycircumventedresistancetoapoptosis by inhibiting BRAFV600E,PI3K, and MAPK.67 In BRAFV600E. mutantATCcells,c-Met-mediatedreactivationofthePI3KAKTandMAPKpathwayssubstantiatesresistanceto vemurafenib,an effect mitigated through the dual inhibition of BRAF and c-Met.68 Similarly,concurrent inhibition of SrcFamilyKinases(Src)and MAPK circumvented resistance to dasatinib,a dual Src/Bcr-Abl inhibitor,by impedingPI3KAKT pathways in vitro.69 Furthermore, the combination of PI3K-mTORinhibitionpotentiatedthereversal ofresistance to palbociclib, a CDK4/6 inhibitor, in ATC.70 These approachesillustratethepotentialoftargetingthePl3K-AKTmTORpathwaytoovercomechemotherapyresistancein ATC,offering new avenues for therapeutic intervention.

Interactionwith otherproteins

Forkhead-box (Fox) family proteins

The involvement of forkhead-box (Fox) family proteins in thePI3K-AKT-mTORpathway ofATCunderscorestheir significance in disease progression.Forkhead box protein A1 (FOxA1）exhibitsheightenedexpressionlevelsinATC，and its suppression results in {\sf G}_{1} growth arrest andreduced cell proliferation.71 Conversely， forkhead box protein M1 (FOxM1）displayssubstantialup-regulationinATCs compared withnormal thyroid tissue and other TC types. ElevatedFOxM1levelscorrelatewithTP53loss-of-function and hyperactivation of the PI3K-AKT-FOxO3a pathway.72 InhibitingFoxM1proveseffectiveinreducingtumorburden and curbing metastasis in ATc.72 Furthermore, Fox03a, a pivotalregulatorintumorgrowth,undergoesAKT-mediated phosphorylation,leadingtoitsexclusionfrom the nucleus. In its non-phosphorylated state at S473，Fox03a remains within the nucleus,promoting ATC proliferation by transcriptionally up-regulating cyclin A1.73 Forkhead box K2 (FOxk2）orchestrates thetranscriptional activationof vascularendothelialgrowthfactorA(VEGFA),which,upon binding to VEGFR1，triggers ERK,PI3K-AKT,and P38-MAPK signaling pathways,fostering angiogenesis.74 This angiogenic process contributes toresistance against apatinib,a VEGFR2 inhibitor, in ATC.74 The intricate involvement of FOXfamilyproteins inATCunderscores theirmultifaceted roles in disease progression and therapeuticresistance.

Sodium-iodide symporter

Sodium iodide symporter(Nis),a pivotal plasma membrane glycoprotein，serves as theconduit for iodide transportation into the thyroid.75 In radioactive iodine (^{131}|) therapy for TC，NISfacilitates the uptake of radioactive iodine into TC cells, effectively impeding tumor growth.76

Experimentalworkhasrecentlygraduallyremovedthe veilovertherelationshipbetweenNISandthePl3K-AKTmTORaxis.Invitrostudiesdemonstratedthatdualinhibition of MEK or B R A F^{\mathsf{V}600E} and PI3Kresulted in anup-regulation of NIS expression.77 Similarly,invivo,MEK inhibition exhibited anup-regulatory effect onsodium-iodine symporterexpression.77The intricateregulation of NISinvolves the PI3K-AKT-mTOR signaling pathway,as evidenced by its modulationbyCTOM-DHP,leading toendogenousNISupregulationconcomitantwiththeinhibitionofPI3K-AKTand MAPK signaling pathways in 8505C ATC cell line.78 Noteworthyassociationsemergedbetweentheexpressionlevels of NIS and PTEN and the grade of TC diferentiation.79 Moreover,inresveratrol-suppressed ATC cells，significant features including PTEN up-regulation and concurrent nuclear translocation of NIS and PTEN were observed.79 This intricate interplayhighlights themultifacetedregulatory networkgoverningNisexpressionanditscorrelationswith the PI3K-AKT-mTOR signaling pathway.

Noteworthily, targeting NIS stands as a challenging target in managing ATC.Radio-active iodine therapy showed its paralysis on the ATC due to the cellular resistance to radio-iodine originating fromtheNISabsence or downregulation.80 There are three innovative approaches for improving the radiotoxicity of ATC, namely nanoparticles, agents,andviruses.i）Nanoparticles.Several novel nanoparticleshavebeendevelopedtoameliorateATC's radiotoxicity,like human serum albumin (HSA) * M n O_{2} R mesoporous silicananoparticles,andtyrosine-hyaluronic acid-polyethyleneimine.80 The lipid-peptide-mRNA nanoparticles experimentally smoothed the radio-iodine therapy for ATC significantly.81 Combination therapy of ^{131}| and other agents (cerebroid polydopamine and indocyanine green) improved the therapeutic effect on ATc.8Radio-sensitization of Prima-1, a TP53 mutant restoring agent, enhances the therapeutic impact of ^{131}| -labelled nanoparticles by reactivating mutant TP53.82 i) Agents. Tunicamycin enhancedtheATCredifferentiationandradio-activeiodine uptake by rescuing the NIS expression,83 and bortezomib facilitated the iodide accumulation and showed a therapeutic effect on ATC.84 Autophagy-activating digitalis-like compoundsincreasedtheexpressionof thyroglobulinand ^{131}| uptake byrestoring NIS significantly, and targeting estrogen-related receptor \boldsymbol{\upgamma} (\mathsf{E R R}γ) by its inverse agonists brought the improvement of NIS function via MAPK signaling pathway inATCcells.86-88Tissue factorTF)presencewas notably high in the THJ-16T ATC cell line, and the combination of two TF-specific agents( ^{64}\mathsf{C u} -NOTA-ALT-836and ^{131}| ALT-836) demonstrated efficacy inmanaging ATC in vivo.89 Furthermore, ^{131}| -labeled caerin 1.1 peptide showcased inhibition of ATC tumor growth and migration.9° ii) Virus. One vaccinia virus, GLV-1h153,is an oncolytic agent against ATC by promotingradio-iodineuptake.91Measles virus-mediated NisS expression has shown its therapeutic effect on ^{131}| -resistant ATC,92 and adenoviral transfer of NIS exhibited itsbestperformanceinincreasingNIS expression and radio-iodine administration at post-transfer day 2.93

Thyroidhormonereceptor \mathbf{β}_{\mathbf{β}}

Theassociationbetweenthyroidhormonereceptor \upbeta (THRβ)and the PI3K-AKT pathway in ATC has gradually comeunderscrutiny.Studiesindicatethatelevated expression of THRβ1 influences differentiation phenotypes and fosters cell proliferation in the ARO ATC cell line.94

Conversely, T H Rβ curtails ATC aggressiveness,_promoting apoptosis by inhibiting the PI3K-AKT pathway.95 This inhibitionisrootedinthedown-regulationofreceptortyrosine kinase (RTK) and the concurrent up-regulation of phosphoinositide and AKT phosphatase in vitro.96 Experiments showcasingselectiveactivationofTHRβhavedemonstrated tumor-suppressive effectsinfemalemice,underscoring its potential therapeutic significance.97 Additionally, T H Rβ exhibitsarestrainingeffectontheactivityofATCcancer stem cells.98,99 Despite these insights，further investigationsarewarrantedtodelineatethepreciseroleof THRβ in thepathology of ATC.Continuedresearchholds promiseforadeeperunderstandingof {\sf T H R}β^{\prime}{\sf S} implications in ATC and its potential as a therapeutic target.

Other frequent gene aberrations

Anaplastic lymphoma kinase

Anaplastic lymphoma kinase (ALK),a receptor tyrosine kinase (RTK), typically governs cell proliferation and survival during nervous system development.Positioned on chromosome 2's short arm (2p23)，ALK frequently undergoes chromosomal recombination with othergenes(X)to formXALK fusion oncoproteins, known as ALK rearrangements.100 These fusion oncoproteins activate ALK,thereby contributing to thepathogenesis ofATC.

Despite theexceedinglylowprevalence ofALKrearrangements in ATC, theirinvolvement in tumorigenesis remains evident.101-106 A comprehensive wholetranscriptomeanalysishighlightedSTRN-ALKfusionasthe mostfrequentinTC.Itsprevalencewasnotablyhigher in PDTC andATC comparedwith other well-differentiated forms.107 The expression of STRN-ALK, coupled with concurrent TP53 loss,instigates thyroid carcinogenesis,leading to multi-step dedifferentiation progressing from PTC to PDTC and ATC in vivo.108

Intriguingly，twonovel pointmutations，C3592T and G3602A, were identified in exon 23 of the ALK gene in ATC.109' Both mutations heightened tyrosine kinase activities and facilitated cell invasion.109 Despite these findings, the precise role of ALK rearrangements in ATC remains enigmatic,necessitating further research for a comprehensive understanding of their impact on the disease.

Cyclin-dependentkinase

Cyclin-dependentkinases(CDKs),a family of serine/threoninekinases,orchestratedistinctphasesofthecellcycle incollaborationwithcyclins andcyclin-dependentkinase inhibitors (CKIs).11o The regulatory action of CKls, comprising the CDK-interacting protein/kinase inhibitory protein (CIP/KIP)family and the inhibitor of kinase (INK) family, modulates CDK activity.CIP/KIP members such as \mathsf{p}21^{\mathsf{c i p}1/} Waf(CDKN1A,o p1), \mathsf{p}27^{\mathsf{k i p}1} (CDKN1B, or p27), and \mathsf{\ p s7}^{\mathsf{k i p2}} (CDKN1) impede CDK function by disrupting CDKcyclin interactions，while theINk family encompassing p 5^{\mathsf{I N K4b}} (CDKN2B, or p15), p16INK4a (CDKN2A, or p16), p 8^{11N/k4c} (CDKN2C, or p18),and \mathsf{p}19^{\mathsf{I N K4d}} (CDKN2D) primarily binds to CDKs.11i'

Maintaining the interplay among CDKs, cyclins,and CKls is crucial for normal cell cycle progression. Mutations affecting CDKs and their partners,particularly CKls,have beenimplicatedintheinitiationandprogressionofATC. Copy number losses and mutations in CDKN2A and CDKN2B have shown associations with ATC.22

ATCexhibitedhighermutationratesinTP53andCDKN2A comparedwithadvancedDTC，withCDKN2Aloss significantlycorrelatingwithpoorerdisease-specificsurvivalin ATC or advanced DTC cases.112 In ATC cases, CDKN2A mutations, either from copy number loss or truncating mutations,weredetectedin5outof8cases,oftenconcurrent with CDKN2B loss,resulting in diminished mRNA expression of both genes.113?

Two key CKIs, CDKN1A and CDKN1B, have shown a profoundassociationwithrestricting ATC cellproliferation. CDKN1A augmented apoptosis when combined withmanumycin and paclitaxel (PTX) in vitro.114 Intriguingly, both CDKN1A and CDKN1B were up-regulated in cell cycle arrest inducedby diverse agents like bone morphogeneticprotein (BMP-7),115 butyrate,116 simvastatin,117 and insulin-like growth factor binding protein 7 (IGFBP7).118 However, furtherexplorationiswarrantedtoelucidatetheprecise roles of CDKN1AandCDKN1B inconstraining ATC cell proliferation.

Telomerasereversetranscriptase

Telomeres,situated atchromosomalends,undergogradual shortening during DNA replication,a process significantly contributing to cellular senescence.Tocounteract this shortening,telomerase,composedoftelomeraseRNA(the lengthening template）andtelomerasereverse transcriptase (TERT, the catalytic subunit), elongates excessively shortened telomeres,enablingDNAreplication and averting cellular senescence.119 Activation of TERT due to mutations immortalizes TC cells,and its underlying mechanisms have beenprogressively elucidated.

TERT mutations are notably prevalent in ATC,ranging from 21% 0 75% 1 and Chinese ATC samples, the frequency of the TERT ^{1,295,228sf{C}>sf{T}} (TERTC228T) mutation was 34.9% (37 samples), showing an association with older patient age (P=0.02) .120 Notably, TERT promoter mutations, especially C228T, tended to co-occur with B R A F^{\mathsf{V}600E} mutation.121

These TERT mutations,particularly in the promoter region，are correlated with poorer prognoses.Within the previously mentioned cohort，a robust association was observed between TERTC228T and distant metastasis in the American subset.120 Long-term survivors of ATC (alive for 2 yearsorlonger)exhibitlowerratesofconcurrentRAS/BRAF and TERTpromoter mutations compared withATC control cases.122 Furthermore, TERT promoter mutations strongly correlatewithincreasedclinicalburdenandanunfavorable prognosis.121 Independently, TERT promoter mutation is linkedwith the anaplastictransformation ofpapillary carcinoma.123 Recurrent papillary carcinomas with anaplastic transformation showcaseahigher prevalence of BRAFV6O0E mutation andTERTpromoter mutationcompared with those without anaplastic transformation.124 These findings highlighttheintricateassociationsbetweenTERTmutations and theclinicaloutcomesinATC.

Tumor suppressor geneP53

Wild-type TP53 serves critical roles in arresting the cell cycle,aiding in DNA repair,and triggering apoptosis when confronted with DNA damage.125 However, in various humancancers，TP53mutationsstripitoftheseessential functions.126

In thecontextofTC,TP53mutationsexhibitasignificant correlation with ATC compared with other types.ATC showcases substantial TP53 up-regulation in contrast to PTC.127 TP53 overexpression is prevalent in anaplastic carcinoma but not in insular carcinoma，suggesting its involvementindedifferentiatingfrom insular thyroidcarcinoma to ATC.128 Additionally, distinct TP53 mutation patternsbetweenFTCandATClesionsfurtherindicatethe specificity_of TP53 mutations in ATC progression.129 Notably，TP53-mutated adenomas may represent precursors for ATC, albeit in a limited proportion.130 Homozygousphenotypesatcodon72ofTP53havebeenidentified as potential risk factors for developing ATC.131

The co-occurrence of TP53 mutations with other genetic alterations is common in ATC.Such combinations，like frameshiftinsertionsinPTENandTP53,havebeenassociated with brain metastasis.132 TP53 and TERT mutations are morefrequentinATCcomparedwithangiosarcomaand PDTC,133,134andTP5mutationwasassociatedwitha shorter survival time.133

ThepreciseroleofTP53mutationsinATCremains elusive.Presently,two primary aspects shed light on this role:i) the functional status of TP53mutations appears to influence theresponse of ATC cellsto evodiamine-induced apoptosis and \mathsf{G}_{2}/\mathsf{M} arrest.135 Gain-of-function TP53 mutations havebeen linked toincreased galectin-3 expression, fostering chemoresistance in ATC.136 Conversely,loss of TP53functionseemstofacilitatethetransitionfrom BRAFV600E-harboring PTC to ATC in vivo.137 In comparison to PTC, ATC exhibits higher levels of a-L -fucosidase-1 (FUCA1), regulated in part by TP53 status,and lower levels of fucosyltransferase-8,resultinginelevatedfucoselevelson cell surface glycans, contributing to ATC aggressiveness.138 ii) TP53 displays intricate interactions with various proteins in ATC.It plays a role as a functional interactor of sox2, influencing ATC stemness regulation.139 Mutant TP53 (G199v) was observed to enhance resistance to apoptosis by suppressing STAT3 in the KAT-18 ATC cell line.140 Notably,TP53 overexpression counteracts the heightened expressionofmini-chromosomemaintenanceprotein7 (MCM7), which is closely associated with tumor malignancy in ATC.141 Furthermore, in vitro studies indicate that decreased junctional adhesion moleculeA(JAM-A) levels in ATC alleviateaggressivenessthrough thephosphorylation of TP53 and 65\mathsf{K}3\mathsf{α}/\upbeta pathways.142

Wnt

TheWnt signalingpathwayorchestratescellularresponses viaextracellularWntsignalsbindingtoaco-receptoronthe cellmembrane,consistingofafrizzledfamilymemberand a low-density lipoprotein receptor-related protein (LRP) family member, and intracellular components (destruction complex)，including glycogen synthase kinase 3 beta (\mathsf{G S K3}\upbeta) ，caseinkinase 1alpha (\mathsf{C K1}α) ，axis inhibitionprotein (AXIN), and adenomatous polyposis coli (APC).143 In the absenceofWntsignals，thedestructioncomplex phosphorylates \upbeta -catenin，marking it for ubiquitylation and subsequentproteasomal degradation,thereby deactivating Wnt target genes.144 However, upon Wnt signal binding to the co-receptor,inhibition ofthe destruction complex ensues,elevating \upbeta -cateninlevelsandactivatingWnttarget genes. 144

TheWntsignalingpathway ispivotal inregulating adult stem cell homeostasis and tissue regeneration，and has implications in thedevelopment of ATC.145Analysis of a JapaneseATCcohortidentifiedmutationfrequenciesof 4.5% for \upbeta -catenin, 9.0% forAPC,and 81.8% for AXIN1,with observed overexpression of Wnt target genes，cyclin D1 (27.3%) and c-myc (59.1%) .146 The abnormal spindle-like microcephaly-associatedprotein(ASPM)was foundto expediteATCprogressionbymodulatingtheWnt/ \upbeta -catenin signaling pathway.147Additionally,hyper-activation of the Wntsignalingpathwaywasassociatedwithresistanceto artemisinin,whichwasovercomebytheWntsignalinginhibitor, pyrvinium pamoate.148 However, a comprehensive understanding ofWntsignaling'sroleinATCremains limited.

Studiesinvolvingtherapeuticinterventionstargetingthe Wnt/ \upbeta -cateninpathwayinATChaveshownpromise.A conditionally replicative adenovirus(named“HILMI")targeting this pathway demonstrated therapeutic efficacy.149 Furthermore,ellagicacidwasfoundtoinhibitATCinvitro by impeding the Wnt/ \upbeta -catenin and PI3K-AKT pathways.150 More comprehensiveresearchfocusing ontargetingtheWnt signalingpathwayinATCtreatmentiswarranted.

Mitochondrialmetabolism

Abnormalitiesinmitochondrialmetabolismplayapivotal role in the pathogenesis and progression of TC,rendering mitochondrial metabolism an enticing therapeutic target for combatting ATC.151 ATC presents distinctive features in mitochondrialmetabolism,with twokey markers，monocarboxylatetransporter1(MCT1）andoutermitochondrial membrane member 20 (TOMM20),being significantly upregulated in ATC compared with non-cancerous thyroid tissue.152 Expression of two mitochondrial enzymes, serine hydroxymethyltransferase-2 (SHMT2） and methylenetetrahydrofolate dehydrogenase2(MTHFD2),correlates with lower thyroid differentiation scores and adverse clinical outcomes in ATC patients.153 Notably, inhibition of SHMT2 disruptsmitochondrialrespiration，exhibiting therapeutic potential in ATC treatment.153 The hyper-activation of mitochondrial one-carbonmetabolism inATC underscores its significance in nucleotide and glycine synthesis.154 Furthermore,compared with PTC or normal thyroid tissue, ATCcellsinducethereleaseofneutrophilextracellularDNA traps associated with mitochondrial reactive oxygen species production.155 Although the precise role of mitochondrialmetabolisminATCtumorigenesisawaitsfull elucidation，targeting mitochondrial metabolism offers a noveltherapeuticavenueforATCmanagement.

Twofacets ofmitochondrial metabolism hold promisein this regard. One is mitochondrial-mediated apoptosis，a focus of intense research as a promising strategy for targeting mitochondrial metabolism.Various agents have demonstratedefficacyinblockingATCcellproliferationby promoting mitochondrial-mediated apoptosis, including 5F,156 diallyl sulphide (DAS),157 and niclosamide.158 Berberine blocked ATC cell proliferation by inducing mitochondrial-mediatedapoptosis andinhibitedmigrationvia MAPK and PI3K-AKT signaling pathways,159 while diallyl trisulfide(DATS)wasfoundtoinducemitochondrial-mediated apoptosisbytriggeringDNAdamagein8505CATCcell line.160 Capsaicin induces mitochondrial calcium overload andsubsequentmitochondrial-mediatedapoptosisinATC cellsby targeting transientreceptorpotentialvanilloid type 1 (TRPV1).161 Bortezomib (proteasome inhibitor) and TRAIL synergistically inhibitedATCcellsbymitochondrialmediated apoptosis.162 The other facet is the mitochondrial membranepotential,emerging as anotherpotentialtarget within mitochondrial metabolism.Two agents,mitotane163 andsodiumorthovanadate,164impededATC cellproliferationbydisruptingmitochondrial membranepotentialand inducing apoptosis.Silencing of MAPK-associateddeath domain-containingprotein(MADD)correlates withreduced mitochondrial membrane potential,165while a combination ofMADD-siRNA and TRAILexhibits therapeutic efficacy in TRAIL-resistant ATC models.166

Additionally, three mitochondrion-target agents aimed atother aspectsofmitochondrial metabolism,artemisinin, artesunate，and ruxolitinib,，arehopeful.Artemisinin inhibits the mitochondrial respiratory chain proteins in CAL62 and BHT-101 ATC cell lines, and CAL-62 cells show drug resistance to artemisinin by blocking pyruvate dehydrogenase.167 Artesunate, the derivative of artemisinin,168 blocks growth andpromotes apoptosis inchemo-resistantKAT-4 ATC cells by impeding mitochondrial functions without affecting glycolysis and acts synergistically with Dox.169 Ruxolitinib promoted apoptosis and pyroptosis in ATC by blockingdynamin-relatedProtein1(DRP1)-mediated mitochondrial fission.170 More comprehensive research focusing ontargetingmitochondrialmetabolisminATC treatment is warranted.

Targetingmitochondrialmetabolismalsoamplifiesthe efficacyofchemotherapyforATC.Atovaquonesignificantlyaugmentstheanti-proliferativeeffectofDoxin vitrobyblockingmitochondrialrespiration and STAT3,171 and combined treatment with octreotide and cisplatin blockedproliferationandinducedmitochondrial-mediated apoptosis in the side population cells of ATc.172 Besides，thecombinationofphotodynamictherapyand carboplatinshowsatherapeuticeffectonATCby breakingmitochondrialmetabolism.Thecombinationof photodynamic therapyandcarboplatinsynergistically enhancedmitochondrialmembranedepolarizationand induced mitochondrial-mediated apoptosisin the FRO ATC cell line.173 In vivo studies validated the synergistic effect of carboplatin and photodynamic therapy on mitochondrialmetabolismandshowedthatthiscombination blocked the expression of EGFR and PI3K while activating PTEN.174 Further investigations are warranted tofully elucidate thevalue of targeting mitochondrial metabolism in enhancing the efficacy and safety of chemotherapy for ATC.

Targeted therapyforATC

Effect and limit of trimodal therapy

All ATC cases are categorized as TNM stage IV (IVA-IVC).175 The standard treatment, known as trimodal therapy, encompasses surgery，chemotherapy，and external beam radiotherapy.175

Trimodal therapystands asa cornerstoneincombatting ATC.Patientsundergoingmultimodaltherapyexperienced a prolonged m0s of 21 months (range,5.8-44),distinctly surpassing those on palliative therapy (mOs, 3.9 months; range, 2.7-5.3)( \mathsf{H R}\ =\ 0.32 P=0.0006 0.176 Aggressive multimodaltherapyledtoaremarkable60-monthmOSfor patients with locoregionally confined ATC，with 50% of casesaliveandfreefromcancer(follow-upduration {>}32 months).177 when compared, patients subjected to trimodaltreatmentdemonstratedanextendedmOsof22.1 months, surpassing those with dual therapy involving external beamradiotherapy andchemotherapy (\mathsf{m o s}=6.5 months; \ P\ =\ 0.0008) .178Radiotherapy doses >=60 Gy correlatedwithimprovedlocoregionalprogression-free survival (\mathsf{H R}\ =\ 0.135 .， {\cal P}=0.001 ）andOs (\mathsf{H R}\ =\ 0.487 B P~=~0.004) ，while trimodal therapy itself was linked to enhanced locoregional progression-free survival (\mathsf{H R}=0.060 ，， P=0.017 .179

However,trimodal therapy revealslimitations across differentstages ofATC.Conventionalchemotherapyand radiationtherapyyieldnoaddedbenefitformoststageIVA patients but do extend survival for IVB patients.180 The differencein \mathsf{m o s} betweenthemultimodalandpalliative therapy groups was notable in stage IVB patients (22.4 vs. 4 months; \mathsf{H R}=0.12 ， 95%C1 :0.03-0.44; ±b{P}=0.0001 ,butnot in stage IVC（ (\mathsf{H R}\ =\ 1.15 .， 95%C1 : 0.4-3.2; ±b{{\cal P}}=0.78 .176 Trimodal therapy prolonged the mOS of stage IVA/B patients compared with surgery alone(25 vs.3 months; P=0.04_{.} ),yetitexhibitednosignificanteffectonthemOS ofstageIvCpatientscomparedwithdebulkingprocedures (6 vs. 7 months; P=0.25 .181while trimodal therapy improvesthesurvivalofregionallyconfinedATCpatients，it cannot effectively control advanced metastatic ATc.182 Challenges in trimodal therapy will be discussed later.

Due to the constraints of trimodal therapy，targeted therapyhasprogressivelyemergedasacrucialaspectof ATCtreatment.TheactivationofeitherRAS-MAPK-ERKor PI3K-AKT-mTOR pathway is mutually exclusive in ATC,and inhibiting_eitherpathwayenhancessensitivitytochemotherapy.183Dualinhibition of B R A F^{\mathsf{V}600E} and MEK significantly reduces tumor size, extent of surgery, and surgical morbidity score.184 Targeted therapy is associated with a favorable OS，and the combination of surgery,radiotherapy，and targetedtherapy (\mathsf{m o s}\:=\:34.3 months; 6- month survival rates = 77.8%) proved most effective.185 Factors linked to improved OS include targeted therapy ⟨{\mathsf{H R}}=0.49 ， 95%C1 : 0.39-0.63; style P<0.001 ),immunotherapy combinedwithtargetedtherapy (\mathsf{H}\mathsf{R}\ =\ 0.58 18 95%C1 0.36-0.94 ， ±b{P}=0.03 ), and surgery accompanied by BRAFtargetedtherapy \begin{array}{r l r}{(\mathsf{H}\mathsf{R}}&{{}=}&{0.29}\end{array} 5 95%C1 ：0.10-0.78; ±b{P}~=~0.02) .186 The discussion on advances in targeted therapy for ATC will follow.

OverviewofcurrentATCtargetingtherapyand immunotherapy

In the current treatmentguidelineforATC,targetedtherapy was recommended for stageIVB-IvCpatients.175For stage IVBcases,dabrafenib and trametinib were recommended as the B R A F^{\mathsf{V}600E} mutation was detected. This combination granted patients for further trimodal therapy. The therapeuticflowofstageIVCcases shared thissolution withstageIVcaseswhencarryingRAFV600Emutation,and immunotherapy targetingPD-1/PD-L1 was recommended underthehighPD-L1expressionortumormutational burdenhigherthantenmutations.However，except dabrafenib-trametinibcombination，therecommended clinicalapplicationofagentstargetingMAPKandPI3K-AKTmTOR signaling pathway was still limited，and immunotherapy was ranked in the conditionalstrength of recommendationwiththelowqualityofevidence.

ThefollowingsectionswilloutlinetheadvancesinATC targeted therapy andimmunotherapyfrom dabrafenib to other candidate agents indetail.Wefoundthat clinical studiesandcasereportsweremainlyconcernedwiththe results of targeting_ MAPK signaling pathway and RAF (especially B R A F^{~600E} ), like lenvatinib, dabrafenib, and dabrafenib-trametinib，and immunotherapy targeting PD1/PD-L1.Reports about drugs aimed at the PI3K-AKT-mTOR signalingpathwayandother targetsmainlyshowedtheir therapeutic potential experimentally, and more clinical stepswerewarrantedfortheirefficacyandsafety.Additionally,theglobal ongoing clinicaltrialsforATCtreatment werealsocollectedandlistedinTable7.Theseclinical trialscanprovidemorecandidateagentsforimprovingthe future prognosis and life quality of ATC patients.

Targeting MAPK signalingpathway

Targeting RTKs

Anlotinib.AsaVEGFR2inhibitor，anlotinibshowedan anti-tumor effect invitro.Anlotinibblocked the angiogenesis in ATC by targeting the CXCL11-EGF-EGFR positive feedback loop.187 Autophagic blockade enhanced anlotinibmediated ferroptosis in ATc.188 A cohort of ATC patients receivinganlotinib-basedchemotherapy (n=25 had 25.1- weekmedianprogression-freesurvivaland96.0-weekmediandisease specificationsurvival,andthe objective remissionrateanddiseasecontrolratewere 60% and 88% ， respectively.189

Apatinib．Apatinib，a VEGFR2 inhibitor，induced both autophagy.andapoptosisbyinhibitingAKT-mTOR pathway.190 It led a 93-year-old female ATC patient to have stable disease with a bestresponse of 19.7% of the primary lesion,sustainedshrinkageoftumorandmetastaticlymph node, and 41-week Os.i91 The combination of ^{125}\dot{I} and apatinib causeda significantreduction in tumor sizein49- year-old female ATC patients.192 In a phase Il trial of apatinib (n~=~17) ，thediseasecontrolratewas 88.2% ，but treatmentwasterminatedin 23.5% of patients due to intolerable toxicity.193 Interestingly， the combination of apatinib andmelittin showed anextra anti-tumoreffectvia caspase-1-GSDMD and caspase-3-GSDME pyroptosis.193

Lenvatinib.Lenvatinib，a multi-tyrosinekinase inhibitor targeting VEGFRs,PDGFRs，and FGFR1，demonstrated significantanti-proliferativeeffectsinATC.Itexhibited promising inhibitory actions on tumorgrowth194andbrain metastasis,195 particularlybyimpedingangiogenesis. Notably, lenvatinib displayed inhibitory effects on BRAFWT/ V600-ATC cells, especially in the presence of pericytes enriched in ATC samples.196 However, no significant correlation was observed betweenVEGFR2 expression in tumor tissue andclinicalresponse tolenvatinib among ATC patients.197

Thedevelopmentofalenvatinib-loadednanocomposite showed therapeutic potential in vivo.198 Combination therapiesinvolvinglenvatinibwithotheragentslike DOX,199 HNHA (a histone deacetylase inhibitor),200 IRAK1/4 Inhibitor1201MEK inhibitors202PTX203andvinorebine204 demonstrated synergistic effects,surpassing the individual agents’impact.Combinationswithanti-PD-1/PD-L1therapy revealed a reduction in polymorphonuclear myeloidderivedsuppressorcellswhilecombininglenvatinibwith anti-Gr-1antibodyshowedanexpandedmyeloid-derived suppressorcell population alongwithenhanced anti-tumor effects compared with lenvatinib monotherapy.205

ClinicalstudiesinvolvinglenvatinibinATCaredetailed in Table 2,showcasing its promising potential in specific cases. Notably,a 68-year-old IVB ATC male patient experienced a 21-month survival post-trimodal treatment,206 anda54-year-oldwomanwithpaucicellularmetastaticATC showed an 18-monthpartial tumor response inlung metastasisafterreceivingalenvatinib-pembrolizumab combination.207

Despiteitspromise,thesafetyand efficacyof lenvatinib areunderscrutiny.Apartfromtheadverseeventslistedin Table2,instanceslikeposteriorreversibleencephalopathy syndrome in a 66-year-old female ATCpatient208 and bilateral pneumothorax in an ATC patient with lung metastasisduringlenvatinibtherapyhavebeenreported.209 Furthermore, the partial response defined in Response Evaluation Criteria in Solid Tumors(RECIST）remainselusiveinsomecasesaftersuccessfullocalcontrolof metastatic ATC (n=3) .210 Notably, a meta-analysis highlighted common adverse events such as hypertension (56.6%) ，proteinuria (32.6%) ， and fatigue" (32%) .211 Addressing thesafetyandefficacyconcerns oflenvatinib willbeimperative infuture studies.

Pazopanib.PazopanibtargetsseveralRTKs(VEGFRs, PDGFRβ,and FGFR1).It inhibited the proliferation of primary human ATC cells,212 and the combination of pazopanib and other agents (like \mathsf{P T X}^{213} or topotecan214) showed more synergisticallyanti-tumoreffect.However,results from clinical trials of pazopanib in ATC were disappointing. In a phase 2 trial ofpazopanibinATC (n=15 )，therewere no confirmed RECIST responses,and treatment was discontinued because of severe adverse events.215 In another phase2trial (n\ =\ 71 )，therewasnodifferenceinmOS between thepazopanib group(5.7months; 95%C1 :4.0-12.8 months) and placebo group (7.3 months; 95%C1 ：4.3-10.6 months) (\mathsf{H R}=0.86 95%C1 :0.52-1.43;one-sided log-rank {±b P}=0.28 .216

Sorafenib.As amulti-targetinhibitor，sorafenibblocks not only RTKs(VEGFRsand PDGFR)but also RAF-1.Sorafenibblockedtheproliferationofvascularendothelial cells stimulated by ATC cells.217 The combinations of sorafeniband otheragentshavebeenexaminedinATC.A combination of sorafenib and metformin218 or H N H A^{219} showedasynergisticallyanti-proliferativeeffectonATC cells andcancerstem cells.Sorafenibcanalsosynergize with other drugs (adavosertib,220 centrinone,221 quinacrine,222 and withaferin \mathsf{A}^{223} ) in blocking the tumor growth of ATC. Besides, the sorafenib-radiation-HNHA224 or sorafenib-radiation- *\mathsf{P T X}^{225} therapy showed therapeutic potential on ATCin vivo.Clinical studies of sorafenib inATC are listed inTable 3.

Sunitinib.SunitinibblockedVEGFR2andPDGFRβ，butit exhibited no effect on the proliferation of ATC cells.217 Combinationofsunitinibandirinotecanshowedsynergistic anti-tumor activity on ATC in vitro and in vivo.226Clinical applications ofsunitinibin treatingATCwerelimited.The combination of radiotherapy,chemotherapy,and sunitinib leda49-year-oldfemaleATCpatienttohaveacomplete response andremains withoutevidence ofdisease more than 18 months after diagnosis,227 and it also caused a reductionintumorsize andcompletemacroscopicresponse in a 79-year-old male ATC patient unfit for systemic chemotherapy treatment.228

Vandetanib.AsaneffectiveinhibitorofVEGFR2/3and EGFR,vandetanibinhibitedangiogenesisanddevelopment ofATCinvivoandinvitro.229,230othlenvatinibandvan detanibblockedtheproliferationandpromotedapoptosis in primary ATC cells,231 and vandetanib showed a more inhibitoryeffectonATCcellproliferationandangiogenesis than sorafenib in vivo.32 However, more clinical trials of vandetanibarenecessarytocheckitsefficacyandsafety.

Targeting RAF (BRAF, BRAFV600E)

Dabrafenib.Dabrafenib demonstratedeffectiveinhibition of CRAF and B R A F^{\mathsf{v600E}} ,inducing G0/G1-arrest by reducing MEK/ERK phosphorylation,presenting a promising avenue for ATC treatment.233 Studies have unveiled the synergistic potential of dabrafenibin combination therapies for ATC. Notably，thecombinedtherapyofdabrafenibwithtrametinib(MEK inhibitor) isrecommended,especially for managing stageIVB/IVCBRAFV600E-positiveATC.175Additionally, invitroobservationsindicatetheanti-tumoreffectsof dabrafenibinconjunctionwithother_agentssuchas axitinib,234e epigallocatechin-3-gallate,235 erlotinib,236 and melatonin.237 However, further independent replications areessentialtovalidatethesafetyandefficacyofthese experimentalcombinationtherapies.Clinicalstudiesand casereports ofdabrafenib inATC are detailed inTables3 and 4，respectively.Despiteitspotential，theefficacyof dabrafenibrequires enhancementdueto severalconfining factors affecting its visceral distribution，including drug lipophilicity,rapid target dissociation，and high albumin binding.238 Moreover, the emergence of {\mathsf{R A C1}}^{\mathsf{P3\bar{4}R}} mutation has been linked to dabrafenibresistancein the anaplastic transformation of PTC.239 Strategies targeting the reactivated RAS signaling pathway, such as SHPO99 (a SHP2 inhibitor)，have shown potential inreversing resistance to dabrafenib in ATC.240 However, a comprehensive explorationintothemechanismsofresistance todabrafeniband relatedsolutionsisyettobeundertaken.

PLX4720. PLX4720, a Specific BRAFV600 inhibitor, restrained the development of ATC in vivo.241 The same effectwasobservedinvivowhencombinedwiththyroidectomy.242 Combination of PLX4720 and anti-PD-1/PD-L1 antibody improved the survival of the murine ATC model,243 and the combination of PLX4720 and oncolyticherpes simplexvirusenhancedtheanti-tumoreffectwithPD-1 blockade.244 More clinical studies are suggested for the potentialtherapeuticeffectofPLX4720.

Vemurafenib.Vemurafenib，acting as a specific inhibitor ofBRAFV00exhibited promisingffectsonTCinvitr5 It enhanced TRAIL-induced apoptosis and，intriguingly, promoted self-renewal in ATC cellsby activating the sonic hedgehog pathway.246 Moreover, in vitro studies demonstratedthatvemurafenibincreasedthecytotoxicityof apigenin247 and tunicamycin248 on ATC and displayed synergistictherapeuticeffectswhencombinedwithmetformin.249 Notably, the inhibition of STAT3 demonstrated a reduction in resistance to vemurafenib in ATC.250 A clinical studyofvemurafenibinATCisoutlinedinTable3,whereit exhibited rapid improvements in the condition of ATC patients，significantly supporting subsequent radiation therapy.251 Case reports also indicated that vemurafenib improved symptoms in patients with specific mutations, such as BRAFV600E and mutant-TP53 (\mathsf{c}.550\mathsf{G})\mathsf{A} p.E180K).252 However, outcomes varied, as seen in the case of a51-year-oldmaleATCpatientwho initiallyresponded tovemurafenibbutexperiencedrapidclinicaldeterioration.253 Further clinical investigations of vemurafenib in ATCare warranted to comprehensively evaluateits efficacy and safety in this context.

Otherpotentialtargeting.WhiletargetingRTKandRAS remains a focus in ATC research,investigations targeting other componentswithin theMAPK signaling pathway are gaining importance and warrant further attention.The prospect of targeting RAS is promising for future therapeutic approaches. Combined treatment involving salirasib (a RAS inhibitor)and modifiedcitruspectin demonstrated therapeutic effects in ATC.254 Similarly, sulforaphane enhanced theefficacyofphotodynamictherapyinATCby specifically targeting the MAPK pathway.255 Expanding beyond trametinib, alternate strategies for MEK targeting inATCarebeingexplored.Forinstance,thecombination of PLX51107(aBETinhibitor)andPD0325901 (a MEKinhibitor) showcasedtherapeuticpotentialinATCbytargetingMYC transcription.256 Intriguingly, while dual inhibition of BRAFV60 andMEKfailed toimpedeSW1736ATCcell migration in 2D culture,it significantly reduced SW1736 cell invasion in 3D culture settings.257 Studies focusing on targetingERKinATCareScarce.InhibitionofERKdimerization emerged as a strategy to suppress ERK activation，ultimatelyimpeding theproliferationandmetastasis ofBRAFmutantATc.58Additionally,epigallocatechin--galate exhibited inhibitoryeffects onATC cellproliferationand induced apoptosisbytargetingtheEGFR-ERKpathway and the cyclin B1-CDK1 complex.259

Targeting PI3K-AKT-mTOR signaling pathway

TargetingPI3K

BlockingPI3Kin ATCwas rarely examined.The cytotoxicity of two heat-shock protein 90 (HSP90） inhibitors，17-AAG and herbimycin A,is associated with the suppression of

PI3K-AKT signaling in ATC.260 Nanoparticles loaded 17-AAG andTorin2blockedATCcellgrowthandimprovedmOSof murine ATC models by targeting VEGFR2.261 Dual inhibition of PI3K and PLK1 also induced apoptosis and suppressed tumorgrowthofATCsignificantly.262Metformininhibited thePI3K-AKT-FOXO1pathwayinSW1736and 8305CATCcell lines but failed toregulate AKT in the C643 cell line and phosphorylationstatusofPI3K,AKT,andFOxO1inallthree ATC cellines.263 Combination of metformin and pioglitazone blocks PI3K-Akt-mTOR pathway and up-regulates several tumor suppressorgenes(includingPTEN)inSW1736 and C643 ATC cell lines.264

Targeting AKT

TargetingAKTinATChasbeengraduallytestedinvitroand in vivo.A combination of MK-2206 (AKT inhibitor) and tyrphostin AG1296(PDGFR inhibitor）inhibited the tumor growth of ATC synergistically.265 Combination of baicalein anddocetaxelsignificantlysuppressedproliferationand inducedapoptosisbydown-regulatingapoptoticand angiogenicproteinexpression andblocking ERK andAkt/ mTOR pathways in ATC.266 High iodine promoted ATC cell proliferationvia AKT-mediatedWee1/CDK1 axis,267 and diallyltrisulphidecompromisedthephenotypeofATC cancer stem cells and restored thyroid-specific gene expression of ATC cells by targeting AKT-SOX2 pathway.268 Both berberine269 and salmonella270 activated autophagy andinhibitedATCtumorgrowthbyblockingtheAKT-mTOR pathway.Aself-assemblepeptidedruginhibitedAKT1at thehalfmaximal inhibitory concentration (1mathsf C_{50}) of 18.2\upmu M and 12.4rm{mu M} in 8305C and 8505C ATC cell lines, respectively.271

Targeting mTOR

ThemTORpathwayhas emerged asapotential therapeutic target in ATC.272 Everolimus, an mTOR inhibitor, demonstrated promising effects in ATC in vitro.273 A phase lIl study involvingeverolimus，encompassing33participants (including7ATCcases),revealed twopatients withpartial responseandstablediseasefor17.9and26months, respectively.274 Notably, one patient exhibited a partial response for 27.9months，while two others hadstable disease for 3.7 and 5.9 months, respectively.275 Combining BP-14(a CDK inhibitor) with everolimus revealed a robust synergistic effect in inhibiting theproliferationofFRO, SW1736, and 8505C ATC cell lines.276 Nevertheless, the presence of a nonsense mutation in TSC2 (\mathsf{T S C}2^{\mathsf{Q1178\star}}) enhanced sensitivity to everolimus,while anmTOR mutation (\mathsf{m}\mathsf{T O R}^{\mathsf{F2108L}}) conferred resistance.277 Comprehensive evaluationsfocusingonbothefficacyandsafetyare imperativetovalidatetheuseofeverolimusinATCtreatment.Apart from everolimus,alternative agents targeting mTOR are being explored.The combination ofAZD6244(a MEKinhibitor）andrapamycindemonstratedsuperior growthinhibitioncomparedwithindividualagents across10 DTC and ATC cell lines.278 Vistusertib effectively overcame resistance to PTX and suppressed ATC tumor growth.279 Additionally, the paeonol-platinum(ll) complex exhibited cytotoxic effects on the SW1736 ATC cellline by downregulating the mTOR pathway,280 while monensin hindered ATCcellproliferationbyimpedingmitochondrialfunction and AMPK-mTOR signaling.281

Otherhopeful targeting therapies

Someothertargetedtherapieshavebeenexploredinthe relentlesspursuitofeffectivetreatmentsforATC.Herewe summarized otherATCtherapiestargetingALK,CDKs,histone deacetylases,TERT, and TP53.

Targeting ALK

Itwasfirstreported that targetingALKby crizotinib(anALK inhibitor)showedanexcellentresponse inanATC case harboring ALK rearrangement.282 Four years later, this case wasfoundtodevelopsecondaryresistance tocrizotinib, andadministering twoALKinhibitors(ceritinibandbrigatinib) brought a therapeutic response to the patient.283 Although thepatient died of locally advanced squamous esophageal cancer induced by radiotherapy, targeting ALK rearrangements is still hopeful in future ATC treatment.

Targeting CDKs

Recognizingthefrequentinactivationofnegativecellcycle regulators and copy number gains of cyclins in ATC,cell cycleinhibitorshaveemergedaspotentialtherapeutic candidates.CDK7 was associated with poor clinical prognosis ofATC，and one of its covalent inhibitors,THZ1，was identifiedbyhigh-throughputchemical screeningand evaluated tobeeffectiveininhibitingtheactivityofcancerstemcells inATC.284285THZ531（acovalentinhibitorofCDK12and CDK13) induced cell cycle arrest and apoptosis by blocking CDK12 in vitro.286 Two CDK4/6 inhibitors, ribociclib and abemaciclib，inducedcellcyclearrestandapoptosisin ATC.287,288AntheDK4/6inhibitor,pabociclib,inded cellcycle arrest in the \mathsf{G}_{0}/\mathsf{G}_{1} phase only in ATC cell lines withCDKN2A/CDKN2Bmutationratherthanthosewithwidetype alternatives.289 Two broad-spectrum inhibitors of CDKs, dinacicliband flavopiridol，showed tumor-suppressing effects onATCinvitro and invivo.290,291In thefuture,new strategies for treatingATC using CDK inhibitors willbe available.

Targeting histone deacetylases

Histonedeacetylaseinhibitorshavebeengradually explored inATC treatment.TheyblockedATCcell migrationandinvasionbyinducingtheexpressionofE-cadherin andpropermembranelocalization of E-cadherin/ \upbeta -catenin complex,292 and improved radioiodine effect in PDTC and ATC byregulating the expression of NIS,thyroid peroxidase, and thyroglobulin.293 Here we summarized three histone deacetylaseinhibitorstestedinATC.

Belinostat

Belinostatreducedtumorsizeinaxenograftmodelof ATC.294 It had a synergistic activity with HSP90 inhibitor NVP-AUY922 in causing cytotoxicity.295 Interestingly, severalhistonedeacetylaseinhibitors(belinostat,vorinostat，and trichostatin A) synergized withHSP90 inhibitor SNX5422 in inducing cytotoxicity,296 while both sodium butyrate and trichostatinA induced apoptosis and differential cell cycle arrest in vitro.297

Panobinostat

Panobinostat induced radioiodine by up-regulating NIs,298 and significant tumor reduction induced by panobinostat was observed.299 Compared with sorafenib and selumetinib,panobinostatshowed maximum cytotoxicityinpatientderivedtumortissueofATCs/PDTCsattheminimum dosage.300

Valproic acid

Explorationofvalproicacid(VPA）incombinationwith variousagentsforATCwarrantsheightenedattention.In vitrostudiesrevealedVPA'saugmentationofDoXandPTX effects.301,32Compared with sole imatinib treatment,the combinationofVPAwithimatinib demonstratedmorepronounced cell cycle arrest.303 vPA prompted apoptosis in the KAT-18 ATC cell line,showing similar effects when combined with Dox，HS-1200 (a synthetic chenodeoxycholic acid derivative), or lactacystin (a proteasome inhibitor).304 Thesynergy of VPA with TRAIL significantly_enhanced apoptosis compared with TRAlL alone in vitro.305 Furthermore,vorinostat and VPA induced cell cycle arrest and raisedPD-L1expression in apatient-derivedPF49ATCcell line.306 In another scenario, VPA sensitized the 8505C ATC cell line to photon irradiation by diminishing DNA damage repair capacity.307 The clinical utility of VPA in ATC remains contentiousandlimited.Areporthighlightedsignificant tumorreduction(by 50.7% viaCTmeasurementand 44.6% via ultrasound measurement)followingcombinedoralVPA, cisplatin, and DoX chemotherapy, radiation, and surgery, sustaininga disease-freestatefor atleasttwoyearspostdiagnosis.308 However, in an Italy-based multicenter randomized controlledphase Il/llltrial,the addition of VPA (1000mg/day) toPTX (80mg/m^{2} /weekly)failedtoimprove progression-free survival or modulate PTX pharmacokinetics.309 The definitive role of VPA in ATC treatment remains uncertain.

Targeting TERT

TargetingTERTinATCtreatmentneedsmoreattention. SilencingofhumanTERTblockedATCcellproliferationand migration significantly.310 Nanoparticles loaded human TERT siRNA showedtumor-suppressioneffect inATC cell lines, and a similar effect was also observed in vivo.311 BIBR1532，a selective TERT inhibitor,induced \mathsf{G}_{0}/\mathsf{G}_{1} cell cycle arrest and apoptosis in SW1736 ATC cell line.312 However,the value of TERTinhibition in treating ATC is yet tobe evaluated deeply.

TargetingTP53

UnravelingthepreciseroleofTP53inATCremainsapriority，yet therapeutic interventions targeting TP53 hold promiseinaddressing thismalignancy.InhibitingTP53has demonstrated efficacy in curbing cell proliferation.HerbimycinA，known for suppressing cell growth，reverses epithelial-mesenchymaltransitionbydeactivatingTP53 and PI3K-AKT signaling in the FRO cell line.313 Conversely, activating TP53 triggers apoptotic responses in ATC cells. Delivery of wild-typeTP53 via adenovirus induces apoptosis,314 while apigenin fosters apoptosis in the FRO ATC cell line by augmenting c-myc levels and TP53 phosphorylation.315′Suberoyl bis-hydroxamic acid promotes apoptosisinvivo through the activation of theNotch1/TP53 signaling pathway.316 The combination of sorafenib and CP31398，a TP53-restoring agent，effectively inhibits cell proliferation in the SW579 ATC cell line.317 Furthermore, modulatingTP53activityaugments theefficacyofradiotherapy inATC.Wild-typeTP53enhances the cytotoxic effects of Nis，heightening the accumulation of betaemitterradionuclidesandtherebyenhancingradionuclide therapy.318 These approaches underscore the potential of TP53-targeted interventions in refining ATC management.

Immunotherapyfor ATC

Tumor immune microenvironment of ATC

ComparedwithotherTCtypes,thetumorimmunemicroenvironmentofATCisuniqueandsomewhatmysterious. The microenvironment of most ATC was infiltrated by macrophages and \mathsf{C D8^{+}} T cells.Compared with PTC,there existsmoreinfiltrationofexhausted \mathsf{C D8^{+}} T cells and M2 macrophages andless cytotoxicityof \mathsf{C D8^{+}} T cells, \boldsymbol{γ}\mathfrak{d}\overline{{\boldsymbol{\mathsf{I}}}} cells,and naturalkiller (NK) cellsinATC,and the levels of immune checkpoint molecules (LAG-3,PD-1,HAVCR-2,and TIGIT) are also elevated.319 Compared with PDTC, the tumor proportionscore of PD-L1was elevated in ATC (7.7% VS. 60% .， P=0.006 )，andtheamountsof \mathtt{C D3^{+}} and \mathsf{C D8^{+}} T cells, {\mathsf{C D}}68^{+} and \mathtt{C D163^{+}} macrophages, and \mathsf{S}100^{+} dendritic cells were also elevated in ATC.320°

Tumor-associatedmacrophages

TAMs emerge as pivotal actors in ATC pathogenesis, particularlyinfosteringmetastasis.Pulmonarymacrophages notably contribute to the pulmonary spread of ATc.321 HumanATCspecimensexhibitrobustinfiltrationof \mathsf{C D68^{+}C D163^{+}} TAMs,322 featuring ramified TAMs. These ramified TAMs intricatelyinterminglewith ATC cells,forming a network through theirramifications,which extend from perivascular clusters and disperse within the tumor parenchyma.323 The abundance of TAMs inversely correlates with ATC prognosis,highlighting the potential of four TAM-related genes (FZD6，RBBP8，PREX1，HSD3B7）aS potential biomarkers.324 A TAM-related prognostic index has been developed,displayingapositiveassociationwithTAMinfiltration levels.324Furthermore, CXCR4 expression significantly correlates with densities of \mathtt{C D163^{+}} TAMS (P=0.013 .325

Immunegeneticsignature

The immunegenetic signature ofATC is alsoyet tobe exploreddeeply.CREB3L1was identified as akeygene in ATCdevelopmentandanupstreamregulatorofdifferentiation-related pathways(including epithelial-mesenchymal transition).326 Most immunogenic cell death genes were highly expressed in ATC,and five genes (TLR4, ENTPD1, LY96,CASP1，and PDIA3)were identified as the dynamic signature in the malignant progression of ATC.327 The T cell immunoglobulin andmucin-domain-containing protein-3 (TIM3)wasidentifiedas animmunecheckpointinmacrophages,328 and TIM3 produced by ATC cells induced tumorpromoting M2-like macrophage polarization.329

Immunotherapyfor ATC

Targeting PD-1/PD-L1

PD-1/PD-L1orchestratesimmunetolerancewithinthe tumor microenvironment,and its targeted inhibition has showcased considerable value in cancer treatment.330

Notably，most ATC cases exhibit positivity for PD-L1, whereasnormalthyroidandDTCpresentwithnegative expression.331 Mean PD-L1 expression markedly elevates in ATC (tumor proportion score =30% ）compared withPDTC (tumor proportion score =5% ±b{\cal P}<0.01 )and normal thyroid tissue(tumorproportionscore =0% .， ±b{{\cal P}}<0.001 ).332 PD-L1 expressioninverselycorrelateswiththeOsofindividuals diagnosed with ATC.33 Differences in PD-L1 expression and lymphocyteinfiltrationdistinguishadvancedDTCfrom ATC.334 Elevated PD-1 expression in inflammatory cells significantlyassociateswithpoorerOS (\mathsf{H R}=3.36 .， 95%C1 1.00-12.96; ±b{P}<0.05 inATC.335

Immunotherapy's primaryfocusin ATCrevolves around PD-1/PD-L1targeting.Synergisticinhibition ofprimaryATC cellproliferationisobservedwiththecombinationof radiotherapy and atezolizumab (PD-L1 antibody).336Moreover, dual inhibition of B R A F^{\mathsf{V}600E} and PD-L1 leads to heightenedlocalTAMlevelsandenhancedtherapeutic nanoparticle delivery.337 Clinical studies and case reports collatingimmunotherapyeffortsinATCaresummarizedin Tables 5 and 6,respectively. These tables offer a comprehensiveviewoftheclinicalapplicationofATCimmunotherapies.They underscore thepredominanttargeting of PD-1 in these therapies(except tremelimumab).Additionally,most immunotherapies in ATC are administered alongsidetargetedtherapyandconventionaltrimodal therapy.However,the outcomes from clinical studies of immunotherapies(Table5)arefewercomparedwiththose of targeted therapies(Tables 2,3)inATC.The development of immunotherapiesfor ATC remains restricted,warranting further exploration and advancement.

Otherpotentialchoices

Beyond thePD-1/PD-L1focus,exploring otherfacets of ATC immunotherapy proves promising.Notably，two key areas show potential:targetingNK cells and delving intoradioimmunotherapy.NKcellsplayapivotalroleintheATCtumor microenvironment.Advanced TCpatients，including those with ATC, exhibit an enrichment of \mathsf{C D56^{h i}C D16^{h i/l o}} NK cells. Compared with circulating \mathsf{C D}56^{\mathsf{l o}}\mathsf{C D}16^{\mathsf{h i}} NK cells, \mathsf{C D56^{h i}C D16^{h i/l o}N K} cells demonstrate increased expressionof CD158a and CD158b(inhibitory KIR family members）and decreased NKG2D (an NK’cell activator).338 These \mathsf{C D}56^{\mathsf{h i}}\mathsf{C D}16^{\mathsf{h i}/\mathsf{l o}} NK cells exhibit higher PD-1 and TIM3 expression and diminished cytotoxicityagainst CAL-62ATC cell lines.Dual blockade of PD-1and TIM3 shows potential in boosting both \mathsf{C D56"}\mathsf{C D16}^{\mathsf{h i/l o}} and \mathsf{C D56^{\mathsf{l o}}C D16^{\mathsf{h i}}N K} cells from ATC patients.338 Additionally, NK cells have shown effectivenessintargetingpumonarymetastasesofACinviv39 andATCcelllineinhibitionwasobservedwithUL16-binding proteins (ULBPs) 2/5/6,which attracted \mathsf{C X C R3^{+}} NK cells.340

InflammatorymarkerofATC

TheeffectivemanagementofATCispivotalincurbingits mortalityrates.Toaidinthis，several inflammatory biomarkers have surfaced as potential facilitatorsin managing ATCpatients.These include thelymphocyte-to-monocyte ratio,neutrophil-lymphocyte ratio(NLR)，platelet-tolymphocyte ratio,and neutrophil-monocyte-platelet-tolymphocyte ratio. Low lymphocyte-to-monocyte ratio levels have emerged as a marker linked topoorer OS amongATC patients.341 Similarly， NLR demonstrates a significant associationwithOS (\mathsf{H}\mathsf{R}\ =\ \ 3.18 5 95%C1 ：1.15-8.85; P=0.026 ，with noticeable differences in OS curves concerning post-radiotherapy NLR (P=0.036) .342 Neutrophilmonocyte-platelet-to-lymphocyteratiostandsoutasanindependentpredictorfortheOSofbothATCandadvanced DTC patients \begin{array}{r l r}{(\mathsf{H}\mathsf{R}}&{{}=}&{6.470;}\end{array} 95%C1 ：2.134-19.616; P=0.001 ).343 Notably, ATC patients experiencing an increaseinNLRfromtheirbaselinevaluesexhibitaworse prognosis compared with those without such elevation.344 However, baseline values of NLR,platelet-to-lymphocyte ratio,and lymphocyte-to-monocyte ratio seem to show no significant differences in Os.344 Despite these observations, theprecisevalue and utility of these inflammatory biomarkersinthecontextofATCmanagementawaitfurther determination.

Discussion

Single-cell RNA sequencing in ATC

Inrecentyears，experimentalstudies ofATC have been empoweredbysingle-cellRNAsequencingtechniques.Besidesthegeneticlandscapeand anaplastictransformation mentioned above,6 more features of ATC were revealed. ATC cellsshowedresistance toDNA damagesfrom \boldsymbol{\Upsilon} -radiation by activating genes associated with homologous recombination and non-homologous end joining,345 and hyper-activationofone-carbonmetabolismwasobservedin the transformation from PTC to ATC.346 Interferon-stimulated gene 15(ISG15） correlated significantly with the proliferationandmalignancyoftheATCcancerstem cells.347 SIGLEC15 deactivated T cells by blocking NFAT1, NFAT2, and N F* K B signaling pathways,and SIGLEC15 inhibition stimulated the secretion of \vert F N-γ and IL-2.348 More subtypesoftumor-infiltratinglymphocyteshavebeen graduallyidentified.OneATC-specificATC-associated macrophage subgroup, 112{\mathsf{R A}}^{+}\mathsf{V S I G}4^{+} TAMs，was identified and associated withthe better prognosis of ATC patients.349 {\mathsf{C X C L13}}^{+} T cells and early tertiary lymphoid structure facilitated the immunotherapy for ATc.350 Future research intoATCrequiresmoreextensiveapplicationofthesinglecell RNA sequencing technique，and the value of spatial RNA sequencing technique，which is rarely deployed in dissecting ATC presently,remains to be examined in the pathogenesis and progression of ATC.

Diagnosis of ATC

Diagnosis of ATC comprises two essential components, invasive tissue sampling，yielding cytological andpathological evidence supported by immunohistochemistry, and imaging modalities, with ^{18}\mathsf{F} fluorodeoxyglucose (FDG) positronemissiontomography/computedtomography (PET/CT) playing a central role in accurate staging.175,351

Invasive tissue sampling

FNA and core needle biopsy (CNB) represent standard minimally invasive tissue sampling techniques.352 FNA has revealedseveralcriticalcytologicalfeatures ofATC including nuclear pleomorphism，coarse/clumped chromatin,macro-nucleoli，apoptosis, and necrosis.353 FNA shows an accuracy rate of 86.5% in diagnosing a cohort of 163 ATC cases,354withinitialultrasonography-guidedFNA achieving a correct diagnosis of ATC in 50% of cases.355 However, the effectiveness of FNA encounters challenges from CNB.In a cohort of 59 ATC cases,CNB shows a higher sensitivityof 87.5% andapositivepredictivevalueof 100.0% for diagnosing ATC than FNA (50.6% and 90.9% ，respectively).356 The rate of diagnostic surgery is significantly lower after CNB (12.5%) than after FNA (35.4%) (P=0.020) .356 Similarity,a meta-analysis reported that CNB showed a higher sensitivity (80.1%) valuefor diagnosingATCthan that of FNA (61%) and exhibited apositive predictive value of 100% for ATC.357 Meanwhile, the need for additional diagnostic surgery after CNB was 17.6% for ATC.357 Sensitivity and specificity of both FNA and CNBin diagnosingATC need more independentexplorationandvalidation.

Immunohistochemistry

Immunohistochemistry plays a crucial role in establishing the diagnosisofATCthroughtissuesampling.Comparative analyses withPTCreveal significantly elevated expression ofcancerstemcellmarkersinATC，notablychemoresistancemarkers,whichcorrelatewithdiminishedoverall survival in ATC cases.358 Moreover, immunohistochemical profilingfacilitatestheidentificationofan8-marker transformationpanelthat exhibits 100% accuracy， sensitivity,and specificity in distinguishing ATC from DTC.359

Two immunohistochemical biomarkersin ATCare worthy of note.One ispairedboxgene8(PAx8).Itwas reported that all three FNA samples of ATC were PAX8 positive.360 PositivePAX8-stainingisreportedinfiveofsevenATCcases mimicking primary head and neck squamous cell carcinoma.361 PAX8 expression was positively correlated with an epithelial pattern (P=0.0008) ,362 a coexisting differentiated thyroid carcinoma component (P~=~0.0004) ,362and improved OS (P=0.019) .363 Meanwhile, another study reported that PAX8 staining was positive in 26 (76%) ATC cases, including all 16 squamodisc variants，7 (58%) giant cell/ pleomorphic variants, and 3 (50%) spindled variants, and all head andnecksquamouscellcarcinomaswerenegativefor PAX8 contrastly.364 Three immunohistochemical features of ATC are proposed: \upbeta -cateninnuclearexpressionwithnoor reduced cell membranous expression,theloss or discontinuouspatternofE-cadherinexpression,and thelossofPAx8 nuclear expression.365 However, the sensitivity and specificityofPAx8indiagnosingATCneedmoreimprovement.In acohortcomprising6casesofATC，allexhibitedpositive staining for pan-cytokeratin，but PAx8 expression was detected in only 40% of these cases.36 In another cohort of 29 ATC cases,the detection rates for thyroid transcription factor-1(TTF-1),PAX8,and E-cadherinwere 17.2% ， 51.7% and 10.3% ，respectively.365 Prostate-specific membrane antigen(PSMA),theotherimmunohistochemicalbiomarkerin ATC，needs more attention.Six of the eight analyzed patients(2 ATCs and 4PDTCs）showedincreasedglucose metabolismwithoutincreasedPSMAuptakeafterPET/CT, whileimmunohistochemical analysis ofPSMA expressionin correspondingpatient tissue samplesreported that there wasstrongPSMAexpressionin27oftheanalyzed 39{\mathsf{A T C}} and 13 of the analyzed 22 PDTC tissue sections.367 There was a correlationbetweenimmunohistochemicalPsMAexpression and uptake on gallium-68 (^{68}\mathsf{G a}) -PMSA-PET/CTinthreeof the examined patients.367In spite of that,the role of PSMA in PET/CT imaging is controversial in ATC.Although ^{68}\mathsf{G a}. PMSA-PET/CTdemonstratedalowerdetectionrate(3/11) thanFDG-PET/CT(8/11)whenvisualizingTClesions(totalof 11 ATC cases),368 it was also reported that ^{68}\mathsf{G a} PMSA-PET/ CT showed high uptake in the primary tumor, cervical, and mediastinal nodes in an ATC case.369

To date,there remains a need for further exploration intothebreadthandeffectivenessofimmunohistochemical biomarkers for diagnosing ATC.Additionally,unlocking the fullpotentialofimmunohistochemistryinelucidating pathological characteristics and monitoring disease progressioninATCis imperative.

^{18}\mathsf{F} -FDG PET/CT

^{18}\mathsf{F} -FDG PET/CT plays a pivotal role in assessing tumor progressionandtailoringdiseasemanagementstrategiesfor ATC patients.175351ATC demonstratesrobust uptaken ^{18}\mathsf{F}. FDG PET images,significantly influencing the clinical management of half of the ATC cohort (16 ATC cases).370 various PETparameters,including elevated maximum standardized uptake value (\mathsf{S U V}_{\mathsf{m a x}}) ，metabolictumor volume,and total lesion glycolysis, are closely associated with adverse prognosis (P<0.001 ， {±b P}=0.002 ,and ±b{{\cal P}}<0.001 , respectively).371 While variations in \mathsf{S U V}_{\mathsf{m a x}} and occurrences of local relapse exhibit no significant correlationpotentially duetothe limited availability of assessable ^{18}\vec{\mathsf{F}} -FDGPET/CTATC cases (less than 50% ,372 both the volume (>=300mL) and intensity (\mathsf{S U V}_{\mathsf{m a x}}\ge18) of FDGuptake emerge as significantprognostic indicators for ATC patient survival.373 The comprehensive assessment of ^{18}\mathsf{F} -FDG PET/CT in diagnosing ATC is elucidated in Table 8，underscoring its considerable diagnostic utility.The future clinical utility of ^{18}\mathsf{F} -FDGPET/CTholds promise for monitoring therapeutic efficacy,374 paving the wayforexpandedapplicationsinATCmanagement.

Prognosis of ATC

Prognosisisadirectindicatoroftreatmentefficacy，and challenges in the treatment of ATCcan be characterized by independent prognosticfactors for their pivotalrolein assessing conditions，guiding treatment decisions，and enhancing survival outcomes.Severalclinicalstudies of independent prognostic factors in ATC have been conducted,375-389and theyhavebeensummarized inTables 9-17. Independent prognostic factors of ATC in these tables can be categorized into three main domains:patient's initial condition，tumor staging,and therapeutic interventions.Subsequentdiscussionwilldelveintothese domains to reveal the challenges in fighting with ATC.

Patient's initial condition

Age

Age at diagnosis basically correlates with inferior OS among patients withATC(Table 9).Age at diagnosis exceeding70 years amplifies the risk among ATC patients (\mathsf{H R}=1.662 ， 95%C1 :1.321-2.092), with a substantial disparity observed incancer-specificmortalityratesper1oo0-person-years betweenindividualsyoungerandolderthan70years (949.980 195%C1 ：827.323-1090.822) VS.1546.667 (95%C| 1333.114-1794.428); \begin{array}{r l r}{P}&{{}<}&{0.001}\end{array} 390 Nowadays, more attention should begiventothe earlyscreeningofATC to decreasetheriskofATCpatients,andtheclassificationof ATC patients may facilitate ATC management,as shown by a valuable tool for risk stratificationbased on age inforecasting the outcomes of ATC patients.391

Clinical presentation

Table10 detailstheprognosticrole of clinicalpresentation, which includes experimental examination,complications, comorbidities, and daily living abilities. This tabulation shows that clinical presentation is controversial for treating ATC.

Onthe onehand，experimentalexaminationof suspicious people can be practical in early-stage screening, diagnosis，and modifying therapeutic schemes.LeucocytosisandNLRhavebeenidentifiedascorrelatingwith inferior OS among ATC patients (Table 10).More independentresearch on the value of experimentalexamination is warranted.

Ontheotherhand,complications atdiagnosiscall for more active interventionsfor their opposingrolesin the prognosis ofATC.Three complications,respiratoryimpairment (Table 10),vocal fold palsy (Table 10)，and dyspnoea,392 have portend a poorer prognosis. Additionally, comorbidities，asassessedbytheCharlson-Deyocomorbidity score, exert a negative effect on prognosis (Table 10).Patients’complications and comorbidities should be appropriately evaluated and handled whenfacing therapeutic options for ATC，and the burden of ATC patients can be lightened extensively.

Tumor staging

TNMstagingisessentialindelineatingtheanatomical extentofATCandestablishingitsstagetoguidetailored treatmentstrategies.It consists of three sections,primary tumor (T)，lymph nodes metastasis (N),and distant metastasis (M).393

The value of three TNM sections in determining prognosis independently has been examined initially.Primary tumors (T status),as detailed in Table 11,can be characterizedbytumorsize,theextentofprimarydisease，and extrathyroidal invasion(extension).Larger tumor size and extrathyroidalinvasion(extension）are correlatedwith reducedOSamongATCpatients,whereasa confined extent ofprimarydiseaseisassociatedwithimprovedOsoutcomes.Lymph node metastasis (N Status),as detailed in Table12,，also showcases itsindependence in determining the prognosis of ATC patients.Nodal classification as negative/unknownimproves OS outcomes,whereas N status as \mathsf{N}_{+}/\mathsf{N}_{\mathsf{x}} indicates decreased OS among ATC patients.A retrospective study (n\ =\ 313) ）reported thatlymphnode metastasisemergesasanindependentriskfactorforATC mortality(adjusted \begin{array}{r l r}{\mathsf{H}\mathsf{R}}&{{}=}&{1.47}\end{array} 5 95%C1 ：1.10-1.96; ±b{P}=0.009 .394Distant metastasis (M Status),as detailed in Table13，correlateswithimpairedOs,andthereexistsa significantdifferencebetweenthewholeATCcohort (n=152) andATCwithdistantmetastasis groups (n=88 一 within the wholecohort in the mortality 76% Vs. 90% ， {P}=0.01 )，survival {>}1 year( 32% Vs. 15% {±b P}=0.003^{\prime} ,and median survival (228.5 vs. 171 days; {±b{P}}=0.01 ).395

Each section of TNM staging can independently influence theprognosisofATC，andbasedontheassessmentofall sections,ATC cases will be classified into stage IVA,stage IVB, or stage IVc.393 Generally, a higher stage denotes a graver risk of ATC patient survival,as outlined inTable 14. ChallengestotheprecisestagingofATCarestillworthyof consideration and solution,and dynamic monitoring of ATC progression urgesfurtherinvestigations onthe exact results and prognostic value of three sections of TNM staging.

Therapeuticinterventions

The efficacy and limitations of trimodal therapy, comprising surgery，chemotherapy，and external beam radiotherapy,havebeen discussed earlier.Recently,each part of trimodal therapy has been gradually scrutinized for its independence in influencing the prognosis of ATC，and theresultfrom suchscrutinization directs thefuture optimization of ATC therapy.

Surgery

Independent impact of surgery on prognosis is outlined in Table 15.Although the decision to undergo surgery correlates with improved OS of ATC patients,a pooled analysis exhibited that surgerybrings higher risk toATCpatients (\mathsf{H}\mathsf{R}=1.997 ， 95%C1 ：1.162-3.433; ±b{P}=0.012 .396Maximum surgical scope and negative surgical margins indicate the

Note:

Note:

prolonged OS of ATC patients. In a retrospective study of 233 stage IVB ATC patients，the super-radical resection group (n=23 )received an improved one-year cause-specific survival rate compared with the no/palliative surgery group (n=80 and 72, respectively) (P=0.0065 .397

Althoughsurgeryhasbeenstronglyrecommendedfor stage IVA and resectable stage IVB ATC patients,175 more efforttoextend and amelioratethe applicationofsurgery is warranted.Tobegin with,increasing the opportunity and wishfor undergoing surgery is vital forthe initial treatment ofATC.ATCpatientswithout thyroidresectionshave older ageand more advancedstagecomparedwithsurgicalpatients (both P<0.001 ).398 Besides, a thyroidectomy should beregularlyperformedtofacilitatefurthertreatmentand improve Os.Finally,radical resection and negative margin shouldbesoughtandcombinedwithother therapiesfor betterclinicaloutcomes.Negativemarginstatuswasmore often achieved instageIVAATCpatients (P<0.001) ，and positivemarginstatuswas associatedwithhighermortality in stageIVA ATCpatients (P=0.017) buthad no influence on the survival of stages IVB and IVC (P>0.05) .398

Chemotherapy

Therole of chemotherapy in theprognosis of ATC seems confusing,as shown inTable 16.Despite the efficacy of and sensitivity tochemotherapyinimprovingOs，some observations showits effect onincreasingtherisk of further survivalofATCpatients.Ameta-analysisalsoreportedthat chemotherapydidnotprolongthesurvival ofATCpatients comparedwithcontrols (\mathsf{H R}\ =\ 0.63 .， 95%C1 ：0.33-1.21;

Note:

Z=1.39 ， ±b{P}=0.17 .399 The therapeutic effect of chemotherapydemandsindependentvalidations andpersonalized chemotherapeuticoptionsshouldbeadvisedfordesirable clinical outcomes.

Radiotherapy

Table17outlinestheprognosticroleofradiotherapy,which showsthesignificantreductionintheriskofATCpatients byradiotherapy.Radiotherapyisadefaultoptionforall stages of ATC patients,175 and the combination of radiotherapyandsurgeryalsoshowcasesexcellentbenefits.One meta-analysisalsoreportedthecombinationofsurgeryand radiotherapysignificantlyreducedtheriskofdeath comparedwithsurgeryalone (\mathsf{H}\mathsf{R}}&{=\phantom{-}0.51 ； 95%C1 .

0.36-0.73; Z~=~3.66 . P~=~0.0002 ）forresectableATC cases,399 and another meta-analysis reported that postoperativeradiotherapy significantlyreduced therisk of deathinallthepatientswithresectedATCcomparedwith those with surgery alone( \mathsf{\Pi}[\mathsf{H}\mathsf{R}=0.556 ， 95%C1 ：0.419-0.737; P<0.001).400

Despitethat,moreeffortiswarrantedintheoptimiza tionof radiotherapy.Onthe onehand，higherradiation dosecorrelateswithimprovedOs.Areasonableelevation of radiation dose is necessary for better clinical outcomes, andsideeffectsdeserveattention.Itwasreportedthat radiation dose >=50 Gy was associated with less dysphagia (odd ratios (0\mathsf{R})=0.2 ， 95%C1 :0.05-0.9; {±b P}=0.029. .4010n the other hand，the optimal technique for administering

Note:

FigureKysigalinpathwaynanalastithyroidcaneifferentathaareblindifferetcolranddife components inthe same pathway are portrayed inthe same color.This pictureiscreated withBioRender.com.

a HR is unavailable and replaced by risk ratio in the original. HR is unavailable andreplacedby theoddratioin theoriginal. HRis adjsted by theere prbability weighting frbalancing variables betwen groups. Cl, confdential intal; H hazad ratio;Ref,reference category.

radiotherapyneedsexamination.Besidesexternalbeam radiotherapy,one radiation delivery technique，intensitymodulatedradiotherapyorvolumetricmodulatedarc therapy,correlates with lower skin toxicity \mathsf{O R}=0.2 ，， 95% CI: 0.04-0.9; P\ =\ 0.045 .401 Comparison among various radiotherapeutictechniquesis essentialfor effectiveATC treatment.

Conclusion

ATC，the most aggressive form of TC，poses significant challenges due to its unclear pathogenesis.Key signaling pathways,namely the MAPK and PI3K-AKT-mTOR pathways (Fig. 1), play pivotal roles in ATC tumorigenesis.Known molecular drivers such as K R A S^{\mathsf{G12D}} and BRAFV600E mutations contribute substantially to this process.Next-generation sequencingofATCsamples(detailedinTable1）hasunveiled additionalgeneaberrationsinALK,CDK,TERT,TP53， andWntpathways,allcrucialinregulatingcellproliferationandhomeostasis.Thesemutationsfoster theimmortality and invasiveness of ATC cells.Additionally, dysfunctionofmitochondrialmetabolismacceleratesATC tumorigenesis，andmitochondrion-targettherapieshave beengraduallyallocatedwithadequateattention,especiallytheirsynergisticeffectwithchemotherapyforATC.

Targeted therapies, outlined in Tables 2-4,have supplementedconventionaltrimodaltherapiesforATC.Agents targetingRTKs(likelenvatinibandsorafenib）andRAF (notablythedabrafenib-trametinibcombination）are under scrutinyfor theirpotentialresponsiveness andpotential to enable curative approaches.However,the efficacyandsafetyofotheragentsintargetedtherapies require more independent clinical studies.While approachestargeting thePI3K-AKT-mTORcascade exhibit diversity，they largely remain inthe experimental phase. Among alternative targeted therapies,CDKs and histone deacetylase inhibitors hold promises for future clinical applications.

Distinctdifferencesinthetumorimmunemicroenvironment distinguishATCfrom other TC types.Dysregulated PD-1/PD-L1expressionandtheirclosecorrelationwith clinicaloutcomeshavespurredtheexplorationand trialsof ATC immunotherapy，detailed in Tables 5 and 6.The amalgamation of immunotherapy，targeted therapy，and conventional treatment could be pivotal in the management of ATC.Beyond PD-1/PD-L1 targeting, experimental approachesinvolving NKcelltargetingandradioimmunotherapyofferinnovativeavenues.Leveraginginflammatory markerspromises rigorous evaluationand precisemanagementof ATC.Abrief graphic summary of theimmunemicroenvironmentofand immunotherapy for ATC is provided in Figure 2.Noteworthily，the globally ongoingclinicaltrials were collectedfromClinicalTrials.gov andlistedinTable7，andwehopethatnoveltherapeutic optionscanbeavailablefromtheseclinicaltrials.

The diagnosis of ATC is based on invasive tissue sampling and imaging modalities.Although FNAreveals the unique cytologicalfeatures of ATC，CNBexhibitsitspotential to replace FNA with higher sensitivity and 100% positive predictivevalue.Theirvalue in diagnosing ATCrequiresfurther exploration.Immunohistochemistry showcases its diagnosticvaluebydisclosingpotentialbiomarkersforATC,and the sensitivity and specificity ofimmunohistochemical biomarkers are worthy of examination andvalidation.As the recommended imaging modality of ATC, ^{18}\mathsf{F} -FDGPET/ CT can detect the unique oncological features of ATC,as shown in Table 8,and several parameters of ^{18}\mathsf{F} -FDG PET/ CT also correlatewithinferior Os,indicating thepromising future in deploying ^{18}\mathsf{F} -FDG PET/CTfor panels specialized in ATC.

Figure2Thetumormmunmicroenvironmentofmmunotherapyfor,andinflammatorymarkerforanaplasticthyroidcane This picture is created with BioRender.com.

Prognosisdirectlyindicatestreatmentefficacy,andindependentprognosticfactors，detailedinTables 9-17， revealtheATCtreatment'sstatusquoandlimitations.To beginwith,thepatient's initial condition should bevalued. Earlyscreeningofsuspiciouspeopleisnecessaryfor reducingtheriskofolder age,and ageshould beconsidered when classifying ATCpatients and administeringpersonalized treatment.Clinical presentations of ATC patients should alsobehandled actively.Experimental examination of specific biomarkers can be developed for early screening and diagnosis，and patients’complications and comorbiditiesshouldbeassessedandcontrolledforbetterclinical outcomes.Moreover,precise evaluation of TNM staging is thecornerstoneofconsideringtherapeuticoptionsand dynamic monitoring of ATC progression. Finally, the value of trimodal therapy， the default therapeutic option，is acknowledged fully. However, improvements in trimodal therapyareencouragedtolessentheburdenandameliorate the OS of ATC patients, such as the extension of thyroidectomy,validation and exploration of chemotherapy, and augmented doses ofradiotherapy.Combiningtrimodal therapy andnew therapy(targeted therapy andimmunotherapy）deserves rigorous evaluation and broadening applications.

CRediTauthorshipcontributionstatement

Zhao Zou: Data curation,Formal analysis, Investigation, Methodology, Visualization,Writing —original draft,Writing -review& editing.Linhong Zhong:Conceptualization, Supervision, Validation.

Conflictofinterests

The authors have no competing interests to declare.

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