Co esponding au ho : Khalida I. Noel
Copy igh © 2025 Au ho (s) e ain he copy igh o his a icle. This a icle is published unde he e ms o he C ea i e Commons A ibu ion License 4.0.
Zombie Cells: Thei Role in Cance De elopmen and Aging wi h Possible Upda es o
The apeu ics Po en ial
Sameh S. Akkila, Khalida I. Noel * and Ahmed F. Hameed
PhD Ana omy, His ology and Emb yology, Assis an P o esso a Human Ana omy Dep ., College o Medicine, Mus ansi iyah
Uni e si y, Baghdad, I aq.
GSC Biological and Pha maceu ical Sciences, 2025, 33(01), 196-205
Publica ion his o y: Recei ed on 12 Sep embe 2025; e ised on 19 Oc obe 2025; accep ed on 22 Oc obe 2025
A icle DOI: h ps://doi.o g/10.30574/gscbps.2025.33.1.0404
Abs ac
Backg ound: Cance is a mul i ace ed diso de ha occu s due o abno mal cells in he body unde going excessi e
g ow h. Al hough he e a e gaps in unde s anding he co e easons behind he escala ion o cance s, some s udies ha e
shed ligh on he ole ha “zombie cells” play in bo h he eme gence and de elopmen o cance . Aged o senescen cells,
mo e in o mally known as “zombie cells,” a e cells ha ha e s opped di iding bu a e s ill me abolically ac i e. They
con ibu e o he aging p ocess and e en he o m o cance hemsel es. This e iew speci ically looks a he ole o
senescen cells in aging and cance , ocusing on hei pa adoxical na u e and whe he hey can be selec i ely
manipula ed o ea men .
Conclusion: The ela ionship be ween senescen cells and he onse o cance is in ica e and mul i ace ed. Senescence
ini ially se es as a cance p e en ion mechanism, bu o e ime, he accumula ion o senescen cells may con ibu e o
he de elopmen o cance h ough a numbe o p ocesses. Impo an ea u es o aging include ch onic in lamma ion
and age- ela ed diseases, bo h o which a e exace ba ed by senescen cells. Ta ge ing senescen cells and hei sec e o y
p ope ies is a no el he apeu ic s a egy o he ea men o cance and age- ela ed diseases. Fu u e esea ch should
ocus on elucida ing he speci ic mechanisms by which senescen cells impac cance de elopmen and aging, as well as
c ea ing e ec i e ea men s a egies, in o de o apply his knowledge o clinical applica ions.
Keywo ds: Zombie Cells; Senescen Cells; SASP; Senoly ic D ugs; Ca -T Cells
1. In oduc ion
Zombie o senescen cells a e cells ha ha e s opped di iding bu emain biochemically ac i e. Due o hei abili y o
ini ia e in lamma ion and al e he issue mic oen i onmen , hese cells ha e been associa ed wi h a ious age- ela ed
diseases, including cance [1].
Think abou ou bodily cells which, while s ill ac i e, a e in a s a e o s asis whe e hey a e no longe di ided. These a e
senescen cells also desc ibed as ‘zombie cells. They a ise om a ious o ms o s ess such as oxida i e s ess, elome e
sho ening, and DNA damage. While he p ima y pu pose o senescence is o hal he p oli e a ion o damaged cells,
some s udies ha e indica ed ha hese cells could aid in he de elopmen o umo s. Thei build-up enables he
de elopmen o di e en ch onic diseases as well [2].
This e iew will discuss he ole o zombie cells in he aging p ocess and cance p og ession, along wi h po en ial
he apies aimed a hese cells.
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1.1. De ini ion and Role o Senescen Cells:
Known as “zombie cells,” senescen cells a e cells ha ha e s opped di iding bu no died. They acqui e a p o-
in lamma o y sec e me called senescence-associa ed sec e o y pheno ype (SASP) and en e a s a e o long-las ing
g ow h a es [3].
1.2. Cha ac e is ics o Senescen Cells
Senescen cells a e cha ac e ized by se e al key ea u es (Fig. 1)
• Cell Cycle A es : They a e s ill me abolically ac i e, bu hey don’ di ide [4].
• Sec e o y Combina ion: They sec e e di e en p oduc s including ma ix me allop o einases, chemokines and
p o-in lamma o y cy okines. This has been e med he Senescence-Associa ed Sec e o y Pheno ype (SASP) [5].
• Epigene ic Changes: P ecise changes in hei his ones and DNA occu [6].
Figu e 1 Cha ac e is ics o Senescen Cells
1.3. Zombie Cells and Cance De elopmen
In he 1960s, in es iga o s i s obse ed ha cells exposed o se e e inju y o s ess can en e a s a e known as
senescence—a s able, i e e sible wi hd awal om he cell cycle o iginally in e p e ed as a sa egua d agains malignan
ans o ma ion [7]. Ye subsequen esea ch has e ealed a mo e nuanced desc ip ion. Ra he han emaining
quiescen , senescen cells equen ly adop a senescence-associa ed sec e o y pheno ype (SASP), eleasing an
asso men o g ow h ac o s, p o eoly ic enzymes, and p o-in lamma o y cy okines ha can pa adoxically os e
umo igenesis, in asion, and me as asis [8].
Empi ical s udies ha e begun o cla i y his dual na u e. Coppé e al. demons a ed ha senescen ib oblas s, h ough
hei sec e ion o in lamma o y cy okines, can ma kedly s imula e he p oli e a ion o adjacen p e-malignan epi helial
cells [9]. Complemen ing hese in- i o indings, Bake e al. employed a ansgenic mu ine model o show ha he
gene ic o pha macological elimina ion o senescen cells subs an ially a enua ed bo h umo g ow h and me as a ic
sp ead [10]. Collec i ely, hese obse a ions sugges ha he apeu ic s a egies aimed a selec i ely a ge ing senescen
cells may hold conside able p omise in he clinical managemen o cance .
1.4. Mechanisms o Senescen Cells in Cance De elopmen
Senescen cells exe hei in luence on cance h ough h ee p incipal ou es, each unde pinned by obus expe imen al
e idence.
1.4.1. Di ec ans o ma ion
On a e occasions, a senescen cell can o e ide i s own g ow h a es and e-en e he cell cycle. This s ep back om
inac i i y is usually d i en by he accumula ion o gene ic lesions and epigene ic d i , e en s ha can culmina e in
ou igh malignan ans o ma ion [11].
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1.4.2. Pa ac ine ins uc ion
E en when senescen cells emain locked in a es , hey a e a om ine . Th ough he senescence-associa ed sec e o y
pheno ype (SASP), hey elease a complex milieu o cy okines, chemokines, and ma ix- emodeling enzymes. These
sec e ed ac o s can ac as po en ins uc o s o neighbo ing cells, p omo ing new blood- essel o ma ion, ampli ying
local in lamma ion, and enabling immune e asion—condi ions ha collec i ely nu u e incipien umo s [12].
1.4.3. Ch onic, low-g ade in lamma ion
Wi h ad ancing age, senescen cells accumula e in issues and sus ain a pe sis en , low-le el in lamma o y s a e o en
e med “in lame-aging.” This endu ing in lamma o y backd op a o s he su i al and clonal expansion o p emalignan
cells, he eby accele a ing cance p og ession [13].
1.5. Senescen Cells in Tumo Mic oen i onmen
Senescen cells a e no sca e ed a andom h ough umo s; hey clus e mos densely along he in asion si e— he e y
edge whe e malignan issue pushes in o heal hy su oundings. F om his s a egic posi ion, hey exe massi e
in luence. Th ough di ec cell- o-cell con ac s and, mo e impo an ly, ia he SASP mix u e hey con inuously elease,
hese cells help c ea e e en s in he umo mic oen i onmen . One s iking example is hei abili y o sound an
immunological ala m: SASP ac o s can signal mac ophages, guiding hei mig a ion owa d he umo edge and he eby
ampli ying he local immune esponse [14].
1.6. Role o SASP in Cance P og ession
The SASP is no a simple on-o -o swi ch; i is a nuanced con e sa ion ha can ei he s imula e a umo o inhibi i
down, depending on con ex [3].
Cuollo e al cap u ed his duali y in he li e . When senescen hepa ic s ella e cells keep hei p53 ci cui y in ac , hei
sec e ed messages a ac mac ophages in o he umo - es aining M1 s a e. Lose p53, howe e , and he same cells
begin o speak an en i ely di e en language—one ha nu u es p emalignan neighbo s and di ec s mac ophages
owa d he p o- umo igenic M2 p og am.
E en mo e s iking, when p53 is expe imen ally e-engaged in a model o ansplan ed li e umo cells, i igge s
senescence and a bu s o chemokines, mos no ably CCL2. This single signal is su icien o call a igo ous wa e o
na u al-kille -cell in il a ion, ipping he balance back owa d umo con ol [15].
1.7. P o-Tumo igenic E ec s o SASP:
Senescen cells, h ough he pleio opic sec e ome designa ed he senescence-associa ed sec e o y pheno ype (SASP),
execu e mul i ace ed and con ex -dependen p o- umo igenic p og ams wi hin he neoplas ic mic oen i onmen . The
ele an mechanis ic modali ies include
1.7.1. Augmen a ion o clonogenic su i al and p oli e a i e capaci y
Cy okines o he SASP—mos p ominen ly in e leukin-6 (IL-6) and in e leukin-8 (IL-8)—engage simila ecep o s o
ac i a e he Janus kinase/signal ansduce and ac i a o o ansc ip ion (JAK/STAT) axis [16]. This signaling cascade
ansc ip ionally ep esses p o-apop o ic machine y (e.g., BAX, PUMA) while concomi an ly up- egula ing cyclin-D1
and c-Myc, he eby con e ing a su i al ad an age and mi ogenic d i e upon p emalignan epi helial clones [17].
1.7.2. Induc ion o epi helial-mesenchymal ansi ion (EMT)
SASP-de i ed IL-6 po en ly ac i a es STAT3, which ansc ip ionally induces he co e EMT ansc ip ion ac o s (Snail,
Slug, Twis ). Consequen loss o E-cadhe in and acquisi ion o imen in and N-cadhe in exp ession gi e mig a o y and
in asi e capaci ies upon neoplas ic cells. Expe imen al e idence in b eas ca cinoma cell lines con i ms IL-6–media ed
EMT and esul ing me as a ic dissemina ion [18].
1.7.3. Neo ascula iza ion ia angiogenic ep og amming
Ma ix me allop o einases (MMP-2, MMP-9) and ascula endo helial g ow h ac o -A (VEGF-A) sec e ed as pa o he
SASP deg ade basemen memb ane cons i uen s and s imula e endo helial cell p oli e a ion, espec i ely. The esul an
angiogenic sp ou ing es ablishes neo- ascula u e indispensable o umo pe usion and me as a ic eme gence [19].
Rec ui men and unc ional pola iza ion o immunosupp essi e leukocy es
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SASP chemokines (CCL2, CXCL12) and cy okines (IL-6, IL-10) os e he in a umo al accumula ion and M2-like
pola iza ion o myeloid-de i ed supp esso cells (MDSCs) as well as he expansion o egula o y T cells (T egs). These
popula ions a enua e cy o oxic T lymphocy e (CTL) ac i i y and na u al kille (NK) cell cy o oxici y, he eby dis up ing
an i- umo immuni y [20].
1.7.4. Ex acellula ma ix (ECM) emodeling and basemen memb ane dis up ion
Sec e ed p o eases, including MMPs and se ine p o eases, deg ade collagen IV, laminin, and ib onec in, acili a ing local
in asion and in a asa ion o malignan cells h ough he comp omised ECM sca old [21].
In o al, he SASP unc ions as a molecula egula o ha , unde oncogenic p essu e, il s he mic oen i onmen al
equilib ium owa d umo p og ession, immune e asion, and me as a ic dissemina ion.
2. An i-Tumo igenic E ec s o SASP
• Immune Su eillance: To s op he de elopmen o cance , SASP ac o s can i s a ac immune cells such as
mac ophages and na u al kille (NK) cells o e adica e p e-malignan and senescen cells. Fo ins ance, SASP-
dependen Th1 and NK cell ec ui men is c ucial in he ea ly s ages o cance o e adica e p eneoplas ic cells
ha a e only beginning o g ow [22].
• Tumo Supp ession: By s opping he g ow h o cells wi h damaged DNA, senescence i sel se es as a de ense
agains cance . Al hough SASP may ha e p o- umo igenic e ec s, senescence as a whole is ypically hough o
as a cance -p e en i e mechanism [23].
2.1. Molecula Mechanisms Th ough Which Zombie Cells In luence Cance De elopmen
SASP, which is p oduced by senescen cells, including "zombie cells," is made up o p o-in lamma o y and p o-
umo igenic subs ances ha p omo e he de elopmen , g ow h, and sp ead o umo s (Fig.2) [24].
Th ough he p oduc ion o ce ain g ow h ac o s, senescen cells encou age cance cell mo ili y and accele a e umo
cell in asion, which is a c ucial s age in cance cell me as asis, ia SASP ac o s [25].
Figu e 2 Molecula Mechanisms Th ough Which Zombie Cells In luence Cance De elopmen [24]
2.2. Using Senescen Cells o P e en Cance
Senescen cells can be ha nessed o p e en cance in se e al ways
• Immune-Media ed Clea ance: Senescen cells can igge he immune sys em o elimina e cance cells since
hey a e immunogenic. Senescen melanoma cells, o ins ance, p oduce CCL5, which encou ages he
ec ui men o umo -in il a ing leukocy es (TILs) and inc eases hei abili y o kill umo cells [26].
• Cance accina ions: Senescen cance cells may be inco po a ed in o accina ions o s op he de elopmen o
cance . Senescen cance cells injec ed in o heal hy animals in mouse models ei he a oided o pos poned he
de elopmen o umo s [27].
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• Senoly ic medicines: such as dasa inib and que ce in, educe he load o SASP ac o s and may lowe he isk o
cance by speci ically killing senescen cells by causing apop osis [28].
• SASP Inhibi o s: Inhibi o s ha a ge pa icula SASP componen s, like IL-6 o TNF-α, can lessen he p o-
in lamma o y e ec s o senescen cells and slow he g ow h o umo s [29].
2.3. Po en ial The apeu ic S a egies Ta ge ing Zombie Cells in Cance T ea men
• Ta ge ing senescen cells and he in lamma o y molecules ha accompany hem, senoly ics and senomo phics
ha e become p omising ea men s o s op umo ecu ence a e ea men ends [30].
• Ta ge ing senescen s omal cells, which in luence he umo mic oen i onmen and cance cells, has been
p oposed as a possible pha macological he apy app oach, o e ing esh insigh s o u he in es iga ion [31].
• Ta ge ing Senescen Mac ophages: Acco ding o a new s udy, senescen mac ophages a e c ucial o he
de elopmen o lung cance . In mice, killing hese "zombie" mac ophages dec eased umo size and leng hened
li e expec ancy, sugges ing a possible new he apy op ion o lung cance [32].
Modi ying he SASP o lessen i s p o- umo igenic e ec s is an addi ional s a egy. Zhu e al. demons a ed ha senescen
cell-induced umo g ow h in mice can be killed by using ansgenic suicide gene. These in es iga ions demons a e he
p omise o SASP a ge ing as a cu ing-edge he apeu ic app oach o he ea men o cance [33].
2.4. Impac o Senescen Cells on Aging
Wi h ad ancing ch onological age, senescen cells accumula e in a wide a ay o issues and o gans. Thei p og essi e
deposi is now ecognized as a undamen al d i e o sys emic aging and a p ecipi a ing ac o in mul iple age-associa ed
pa hologies. The mechanis ic consequences can be dis illed in o h ee in e - ela ed axes:
2.4.1. Ch onic low-g ade in lamma ion (“in lamm-aging”)
The senescence-associa ed sec e o y pheno ype (SASP) eleases a sus ained milieu o p o-in lamma o y cy okines—
no ably IL-6, IL-8, TNF-α, and MCP-1— ha p opaga e s e ile, sub-clinical in lamma ion h oughou he o ganism. This
pe sis en in lamma o y one is epidemiologically and causally linked o me abolic synd ome, ype 2 diabe es melli us,
a he oscle o ic ca dio ascula disease, and neu odegene a i e diso de s [34].
2.4.2. Tissue a chi ec u al de e io a ion and unc ional decline
SASP-de i ed ma ix me allop o einases (MMPs), se ine p o eases, and glycosidases emodel he ex acellula ma ix
(ECM), leading o collagen c oss-linking, elas in agmen a ion, and basemen -memb ane dis up ion. These al e a ions
comp omise biomechanical in eg i y and dis u b pa ac ine signaling ne wo ks, culmina ing in o e issue dys unc ion
[35].
2.4.3. E osion o issue homeos asis and egene a i e ese e
Senescen cells sec e e TGF-β amily ligands, ac i in A, and Wn an agonis s ha impose cell-cycle a es and lineage
wis ing on esiden s em and p ogeni o popula ions. The esul an a enua ion o p oli e a i e and di e en ia ion
capaci y unde mines endogenous epai mechanisms and accele a es age- ela ed issue e osion [36].
In conce , hese ha m ul e ec s posi ion cellula senescence as a cen al pilla o he aging p ocess and a con ollable
he apeu ic a ge o ex ending heal h span.
2.5. Addi ional Insigh s
Mechanis ic Con ibu ions o Senescen Cells o Oncogenic E olu ion
2.5.1. Acquisi ion o oncogenic gene ic lesions
O e p olonged esidence in issues, senescen cells accumula e s ochas ic DNA damage and eplica i e s ess–induced
mu a ions. The concomi an SASP-media ed p o-in lamma o y milieu po en ia es mu agenesis by inc easing oxida i e
and ni osa i e s ess, he eby acili a ing he ansi ion om senescence o malignan ans o ma ion [37].
2.5.2. Epigene ic ep og amming o he SASP
Age-associa ed al e a ions in DNA me hyla ion pa e ns, pos - ansla ional his one modi ica ions, and ch oma in
accessibili y wi hin senescen cells econ igu e ansc ip ional ne wo ks. These epigene ic shi s ampli y he exp ession
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o p o- umo igenic SASP ac o s, e ec i ely con e ing he senescence p og am in o a d i e o neoplas ic p og ession
[38].
2.5.3. O ches a ion o immune e asion
Senescen cells sec e e immunomodula o y media o s—including TGF-β, IL-10, VEGF, and PD-L1— ha ec ui
egula o y T cells (T egs) and myeloid-de i ed supp esso cells (MDSCs) while simul aneously a enua ing cy o oxic T-
lymphocy e and na u al-kille -cell e ec o unc ions. This immunosupp essi e mic oen i onmen pe mi s budding
cance clones o escape immune su eillance and pe sis [39].
3. Ca -T Cell The apy and Zombie Cells
Rega ding cance and aging, he e is a connec ion be ween CAR T-cell he apy and "zombie cells" (senescen cells).
Immune cells known as CAR T-cells we e de eloped wi h he exp ess pu pose o iden i ying and des oying cance cells
[40]. A pa ien 's T cells, a subse o whi e blood cells, a e ex ac ed and al e ed in a lab o exp ess a chime ic an igen
ecep o (CAR) as pa o CAR T-cell he apy. This CAR a ac s speci ic an igens on cance cells, which he T cells can
ecognize and adhe e o, des oying he cells. Despi e i s ema kable success in ea ing ce ain blood cance s, CAR T-
cell he apy s ill has d awbacks, such as umo esis ance and po en ial oxici y [41]. Senoly ics may be able o e adica e
senescen cells by imp o ing he umo mic oen i onmen and educing in lamma ion, which would make he umo
mo e suscep ible o CAR T-cell he apy. Al hough he e is ongoing esea ch o de e mine he mos e ec i e s a egies
o combine senoly ics wi h CAR T-cell ea men , senoly ics can also ha e o - a ge e ec s. Senescen cells a e being
in es iga ed as a sou ce o an igens o CAR T-cell a ge ing (Fig. 3) o as a accina ion o inc ease an i- umo immuni y
[42].
Figu e 3 Senescence in cance , ole o senili ies and CAR-T cells (43)
To pu i simply, knowing how senescen cells unc ion in cance and aging is essen ial o imp o ing CAR T-cell he apy
and c ea ing esh s a egies o ea ing age- ela ed illnesses and cance .
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3.1. Fu u e Resea ch Di ec ions
• Mechanis ic S udies: To cla i y he p ecise molecula p ocesses by which senescen cells a ec he ini ia ion
and sp ead o cance , mo e in es iga ion is equi ed.
• The apeu ic Ta ge s: Mo e po en cance ea men s may esul om he disco e y and con i ma ion o no el
he apeu ic a ge s in SASP and senescen cells.
• Clinical s udies: Tes ing he e ec i eness o SASP inhibi o s and senoly ic medica ions in cance pa ien s
h ough clinical s udies may yield impo an in o ma ion abou hei possible he apeu ic ad an ages.
• Combina ion The apies: Resea ching he use o senoly ic medica ions in conjunc ion wi h cu en ly a ailable
cance ea men s may imp o e ea men esul s and lowe he chance o ecu ence.
• Bioma ke s: C ea ing bioma ke s o iden i y and ack senescen cells in cance pa ien s may help in ea ly
cance de ec ion and ea men .
• Resea che s may be able o imp o e cance ea men and p e en ion by c ea ing new he apeu ic app oaches
o a ge senescen cells and hei sec e o y pheno ype by comp ehending he complex in e ac ion be ween
hese cells and cance .
4. Conclusion
Senescen cells and he de elopmen o cance ha e complica ed and mul idimensional in e ac ion. Al hough he
buildup o senescen cells o e ime can con ibu e o he p og ession o cance h ough a a ie y o mechanisms,
senescence ini ially ac s as a p e en i e mechanism agains cance . Senescen cells also con ibu e o age- ela ed
illnesses and ch onic in lamma ion, which a e impo an aspec s o aging. A new he apeu ic app oach o he ea men
o age- ela ed illnesses and cance is o a ge senescen cells and hei sec e o y cha ac e is ics. In o de o use his
in o ma ion o clinical pu poses, u u e s udies should concen a e on cla i ying he p ecise p ocesses by which
senescen cells a ec he aging and de elopmen o cance as well as de eloping e icien ea men app oaches.
Compliance wi h e hical s anda ds
Disclosu e o con lic o in e es
No con lic o in e es o be disclosed.
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