Co esponding au ho : D . Anshika S i as a a
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.
F om dysbiosis o umo p og ession: he mic obiome’s ole in head and neck
squamous cell ca cinoma (HNSCC)
Anshika S i as a a , Bha ika Sain, Abhilasha Fenin, Ashmeen Kau and Aa ohi Punj
Depa men o O al Pa hology, Adesh Ins i u e o Den al Sciences & Resea ch, Ba hinda-151001, Punjab, India.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 26(02), 2555-2562
Publica ion his o y: Recei ed on 30 Ma ch 2025; e ised on 14 May 2025; accep ed on 17 May 2025
A icle DOI: h ps://doi.o g/10.30574/wja .2025.26.2.1782
Abs ac
Head and neck squamous cell ca cinoma (HNSCC) is one o he leading heal h issues globally. O al ca i y ha bo s a ich
a ie y o mic obes, which a e in cha ge o p ese ing homeos asis unde heal hy ci cums ances. Imbalance among his
mic obial communi y—is e e ed o as o al dysbiosis— ha has he po en ial o cause oncogenesis by ch onic
in lamma ion, immune modula ion, and geno oxic e ec . Pa hogenic bac e ia, including Po phy omonas gingi alis,
Fusobac e ium nuclea um and T eponema den icola ha e been linked wi h he de elopmen & p og ession o umo s.
Dysbio ic mic oen i onmen is capable o causing DNA damage, inducing epi helial-mesenchymal ansi ion, and
emodeling he umo mic oen i onmen , hence acili a ing cance de elopmen and p og ession. The cu en e iew
aims a ackling he mul i ace ed ela ionship be ween o al dysbiosis and head and neck squamous cell ca cinoma
(HNSCC) in ligh o unde lying molecula mechanisms, po en ial diagnos ic applica ion and he apeu ic measu es.
Keywo ds: O al ca i y; Squamous cell ca cinoma; O al dysbiosis; Ca cinogenic; Tumo ; Po phy omonas gingi alis;
Fusobac e ium nuclea um; Tumo mic oen i onmen ; Oncogenesis
1. In oduc ion
Head and neck squamous cell cance (HNSCC) anks amongs he mos equen malignan malignancies o he head &
neck [1], quali ying i o become a p ime uni e sal heal h ocus a ea. This li e- h ea ening cance has bleak p ospec s
when ea ed wi h ad anced gene a ions o adiochemo he apy ea men s; he e o e, he e is a need o ea ly
ecogni ion wi h in ensi ied e o s owa ds he apeu ic ea men [2]. Risk ac o s such as obacco use, alcohol
consump ion, and in ec ion wi h human papilloma i us (HPV) a e es ablished, bu he e is eme ging e idence o
suppo he in ol emen o he o al mic obiome in ca cinogenesis [3].
The human o al ca i y con ains a ich mic obial communi y ha includes bac e ia, ungi, i uses, and a chaea and is
essen ial in ensu ing o al and sys emic heal h [4]. Unde heal hy s a es, commensal bac e ia like S ep ococcus and
Veillonella play oles in immune homeos asis and pa hogen esis ance. Ye , al e a ions in mic obial balance—also
known as o al dysbiosis—can esul in ch onic in lamma ion, immune e asion, and umo -p omo ing ac ions [5].
In e es ingly, oppo unis ic pa hogens like Po phy omonas gingi alis, Fusobac e ium nuclea um, and T eponema
den icola ha e been shown o p omo e oncogenic pa hways h ough immune modula ion, bac e ial me aboli es, and
geno oxic e ec s [6]. Some ecen s udies indica e ha o al mic obial dysbiosis can be bo h a bioma ke and a a ge
o he apeu ic in e en ion o HNSCC [7]. Elucida ing he umo -mic obiome ela ionship is pi o al o he
de elopmen o p ecision oncology. In his e iew, he complex in e ac ion be ween o al dysbiosis and HNSCC is
discussed, highligh ing ca cinogenesis mechanisms, diagnos ic, and no el he apeu ic app oaches.
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2. O al mic obiome
The o al ca i y shel e s a dynamic and mul i ace ed mic obial communi y consis ing o mo e han 700 species o
bac e ia, in addi ion o ungi, i uses, and a chaea [8]. This mic obial communi y is i al o bo h o al and sys emic heal h,
as i moni o s immune esponses, inhibi s coloniza ion by pa hogenic mic obes, and con ibu es o i al me abolic
p ocesses [9]. O al homeos asis depends on a balanced o al mic obiome, bu mic obial composi ion dis u bances—o al
dysbiosis—can cause a numbe o diseases, such as pe iodon i is and ca ies, and possibly head and neck squamous cell
ca cinoma (HNSCC) [10].
2.1. Composi ion o he O al Mic obiome
The o al mic obio a comp ises commensal and pa hogenic mic obes ha a e in ha mony wi h he hos in a inely uned
balance. Commensal bac e ia like S ep ococcus, Veillonella, Ro hia, and Neisse ia, which play oles in immune
modula ion and p e en ing pa hogen o e g ow h [9], a e mos ly ound in heal hy indi iduals. They se e o main ain
o al pH, b eak down die a y cons i uen s, and communica e wi h he immune sys em o modula e in lamma o y
p ocesses [11].
Dysbiosis, on he o he hand, in ol es an accumula ion o pa hogenic species such as Po phy omonas gingi alis,
Fusobac e ium nuclea um, and T eponema den icola—mic obes ha a e well known o hei in ol emen in
pe iodon i is and, mo e ecen ly, in ca cinogenesis [12]. They play oles in immune e asion, ch onic in lamma ion, and
he p oduc ion o oncogenic me aboli es [6].
2.2. The Mic obiome’s Role in Immune Homeos asis
The o al mic obiome is also impo an in modula ing immune esponses. Immune sys em ac i i y is con olled by
commensal bac e ia h ough he s imula ion o pa e n ecogni ion ecep o s (PRRs), e.g., Toll-like ecep o s (TLRs), o
ensu e immune homeos asis [13]. Immune ole ance is enhanced by a heal hy mic obiome h ough cy okine egula ion,
including in e leukin-10 (IL-10), which is an i-in lamma o y [14]. On he o he hand, o al dysbiosis may in e e e wi h
immune egula ion o induce a p o-in lamma o y condi ion wi h inc eased le els o umo nec osis ac o -alpha (TNF-
α), in e leukin-6 (IL-6), and in e leukin-8 (IL-8)—all o which play a ole in umo g ow h [15]. Bac e ial dysbiosis-
induced ch onic in lamma ion could be esponsible o he de elopmen o a mic oen i onmen a ou ing
ca cinogenesis, acili a ing malignan ans o ma ion o he o al epi helium [16].
2.3. Dysbiosis as a Disease P ecu so
O al dysbiosis is long es ablished in pe iodon al disease and ca ies, bu g owing e idence indica es ha i plays a ole
in sys emic diseases such as ca dio ascula disease, diabe es, and e en neu odegene a i e diso de s [17]. O pa icula
in e es , ecen e idence has shown ha mic obial dysbiosis has a s ong associa ion wi h he de elopmen o HNSCC,
and i is p oposed ha ce ain bac e ial communi ies may play a ole in cance ini ia ion and p og ession [18].
Fo example, F. nuclea um—a pe iodon i is-associa ed bac e ium—has been ound o induce epi helial-mesenchymal
ansi ion (EMT), acili a e immune e asion, and enhance esis ance o apop osis in cance cells [19]. Likewise, P.
gingi alis can cause DNA damage and supp ess no mal epai mechanisms o epi helial cells, u he aiding
ca cinogenesis [20].
These da a indica e ha p ese a ion o o al mic obial homeos asis is no me ely c i ical o a oidance o pe iodon al
disease bu po en ially also holds ele ance o p e en ion o cance . Fu he elucida ion o he unc ion o he
mic obiome in he egula ion o he immune sys em and disease de elopmen can open he way o new diagnos ics
and he apies aiming a mic obial dysbiosis.
3. O al dysbiosis and ca cinogenesis
The e ha e been nume ous s udies pe o med in ecen imes o asce ain he connec ion be ween o al dysbiosis and
ca cinogenesis ha d ew monumen al a en ion [21]. O o-pa hogens can manipula e he umo mic oen i onmen by
se e al ways, i.e., ch onic in lamma ion, immunosupp ession, bac e ial me abolism, and geno oxici y di ec ly [22].
These p ocesses g an a suppo ing niche o he malignan ans o ma ion [23].
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3.1. Mechanisms linking dysbiosis o HNSCC
3.1.1. Ch onic In lamma ion and Ca cinogenesis
In lamma ion is a body’s na u al p ocedu e which occu s in esponse o any in ec ion o inju y o p omo e be e &
as e healing . I can be acu e o ch onic. Ch onic in lamma ion is well-es ablished hallma k o cance [24]. P. gingi alis
and F. nuclea um igge he nuclea ac o kappa B (NF-κB) and mi ogen-ac i a ed p o ein kinase (MAPK) signaling
pa hways, leading o p oduc ion o p o-in lamma o y cy okines i.e. in e leukin-6 (IL-6), umo nec osis ac o -alpha
(TNF-α), and in e leukin-8 (IL-8) [25]. In lamma ion las ing o longe du a ion p oduces eac i e oxygen & ni ogen
species (ROS & RNS), inducing DNA damage, genomic ins abili y, and epigene ic modi ica ions— which a e he p ima y
e en s in ca cinogenesis [24].
3.1.2. Mic obial Me aboli es and Oncogenesis
O al bac e ia yield me aboli es ha may con ibu e o oncogenesis. Fo ins ance, some anae obic bac e ia, o ins ance,
F. nuclea um and P. gingi alis, p oduce sho -chain a y acids (SCFAs) like bu y a e and p opiona e, which could
comp omise epi helial cell in eg i y and ampli y umo -p omo ing pa hways [25]. Mo eo e , ni osamine o ma ion by
Neisse ia and Haemophilus species is o speci ic in e es . Ni osamines a e es ablished ca cinogens ha esul in DNA
alkyla ion, mu agenesis, and enhanced oxida i e s ess, which play a ole in malignan ans o ma ion [26].
3.1.3. Immune E asion and Tumo P og ession
E asion o immune su eillance is one o he cha ac e is ics o cance . E asion occu s h ough mechanisms ha ha e
been de eloped by ce ain o al pa hogens so ha hey may inhibi immune unc ion and hus shield umo cells om
being de ec ed. P. gingi alis, o ins ance, inhibi s apop osis o in ec ed epi helial cells by in e e ing wi h Bcl-2 amily
p o eins and hus allows long- e m su i al o ans o med cells [27]. Mo eo e , F. nuclea um is ound o in e ac wi h
Toll-like ecep o s (TLRs) and β-ca enin signaling, supp essing T-cell esponses and p omo ing immune e asion [28].
In e ac ions like his esul in uncon ollable cance cell g ow h.
3.1.4. Geno oxic E ec s and DNA Damage
Se e al o al pa hogens p oduce a chemical named geno oxin which is esponsible o causing DNA damage and genomic
ins abili y. Fo ins ance, P. gingi alis p oduces gingipains, a class o p o eases ha deg ade hos p o eins and acili a e
mu agenic changes [29]. Simila ly, F. nuclea um has been linked o double-s and DNA b eaks, which p omo e
ch omosomal ins abili y—a key ea u e o cance p og ession [3].
4. The mic obiome- umo mic oen i onmen in e play in HNSCC
The umo mic oen i onmen (TME) plays a c ucial ole in cance p og ession, in luencing umo cell p oli e a ion,
immune e asion, and he apeu ic esis ance. Se e al s udies indica e ha o al mic obio a has he po en ial o shape he
TME in HNSCC by modula ing he in lamma o y pa hways, me abolic in e ac ions & immune esponses [30].
4.1. In lamma ion-D i en Tumo Mic oen i onmen
Pe sis en in lamma ion is one o he cha ac e is ics o he mic oen i onmen o HNSCC, and o al pa hogens play an
ac i e ole in his in lamma o y p ocess. Po phy omonas gingi alis and Fusobac e ium nuclea um cause ch onic
in lamma o y signaling h ough he ac i a ion o he nuclea ac o kappa B (NF-κB) and Janus kinase/signal ansduce
and ac i a o o ansc ip ion (JAK/STAT) pa hways [24]. These pa hways esul in inc eased p o-in lamma o y
cy okines like:
• Tumo nec osis ac o -alpha (TNF-α) – I p omo es angiogenesis and su i al o umo cell.
• In e leukin-6 (IL-6) and In e leukin-8 (IL-8) – Responsible o cance cell p oli e a ion and in asion.
• T ans o ming g ow h ac o -be a (TGF-β) – P omo es epi helial-mesenchymal ansi ion (EMT), acili a ing
me as asis [15].
4.2. Immunosupp essi e E ec s o Dysbiosis
The immune esponse is key o managing umo g ow h, bu o al pa hogens ha e he abili y o es ablish an
immunosupp essi e mic oen i onmen suppo ing cance g ow h (see igu e 1 ) [13].
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Figu e 1 Flowcha ep esen ing he immunosupp essi e e ec s caused by o al dysbiosis
The in e play o ch onic in lamma ion, immune supp ession, and checkpoin ac i a ion es ablishes a umo - pe missi e
mic oen i onmen , making HNSCC esis an o immune-media ed clea ance.
4.3. Mic obial Me aboli es and Tumo Me abolism
Oncogenic me aboli es a e p oduced by he o al pa hogens o sus ain he umo g ow h. Me aboli es like sho chain
a y acids (SCFAs), polyamines & bac e ial lipopolysaccha ides (LPS) play an impo an ole. These me abolic
in e ac ions unde sco e he ways in which o al mic obio a a ec umo g ow h independen o di ec in ec ion, poin ing
o new di ec ions o me abolic- a ge ed he apies in HNSCC ea men . Sho chain a y acids (SCFAs) like bu y a e
and p opiona e may play bi alen oles—bo h umo supp esso s du ing no malcy and umo p omo e s du ing
dysbiosis [31]. Polyamines like pu escine and spe midine om P. gingi alis p omo e cance cell g ow h and apop osis
esis ance [32]. Bac e ial lipopolysaccha ides (LPS) s imula e Toll-like ecep o s (TLRs) on immune and umo cells,
p omo ing umo - acili a ing in lamma ion [33].
4.4. Bio ilms and Thei Role in Tumo Agg essi eness
Bio ilms a e communi ies o mic obes ha a e enclosed in an ex acellula ma ix. I ac s as a “p o ec i e co e ing” o
he encased mic obes p e en ing hem om ha sh en i onmen [34]. Bio ilm bac e ia p oduce a p o- umo igenic niche
h ough:
• Inc eased esis ance o chemo he apy by ele a ed ex acellula ma ix p oduc ion, which hinde s d ug
pene a ion[35].
• Inducing epi helial-mesenchymal ansi ion (EMT) and umo in asion [35].
• C ea ing hypoxic condi ions, esul ing in ascula iza ion and umo g ow h [35].
Ta ge ing bio ilms by an i-bio ilm agen s o in e e ing wi h bac e ial communica ion (quo um sensing inhibi o s) is a
new app oach in mic obiome- a ge ed cance ea men .
5. The ole o he mic obiome in ea men esponse and esis ance in HNSCC
The o al mic obiome's composi ion has inc easingly been unde s ood as a c i ical de e minan o ea men e icacy
and esis ance in head and neck squamous cell ca cinoma (HNSCC). Dysbiosis can a ec he e ec i eness o
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adio he apy, chemo he apy, immuno he apy, and a ge ed he apies, in luencing ou comes o pa ien s. Explo ing he
ole o he mic obiome in he apeu ic esis ance may unlock new possibili ies o pe sonalized he apy s a egies in
HNSCC [7].
5.1. Mic obiome and adio he apy esponse
5.1.1. Mic obial Modula ion o Radia ion Sensi i i y
The bac e ial ecosys em in he o al ca i y can be easily al e ed by adia ion, esul ing in inc eased le el o pa hogenic
mic obes. These bac e ia a e in ol ed in in lamma ion and delayed mucosal healing, impai ing ea men compliance
and pa ien ou come. On he o he hand, some commensal bac e ia (S ep ococcus and Lac obacillus spp.) ha e
adiop o ec i e p ope ies, which indica e ha modula ion o he mic obiome may p e en mucosi is se e i y [6].
5.1.2. Mic obiome-Induced Radio esis ance
P. gingi alis and T eponema den icola s imula e DNA damage epai mechanisms, ensu ing umo cell su i al a e
adia ion [10]. Mo eo e , umo hypoxia, which is caused by he mic obio a, also leads o adio esis ance because
hypoxic umo cells a e less sensi i e o ionizing adia ion [3]. E icien s a egies speci ically a ge ing he mic obes a e
p obio ics & an ibio ics o downg ade he le el o bac e ial popula ion & enhance adio he apy e icacy.
5.2. Chemo he apy and mic obiome in e ac ions
Chemo he apeu ic d ugs, such as cispla in and 5- luo ou acil (5-FU) a e widely used in he ea men o HNSCC.
Ne e heless, he o al mic obiome impac s d ug me abolism, ac i i y, and oxici y conside ably.
5.2.1. Mic obial Me abolism o Chemo he apeu ic Agen s
Mic obial enzymes a e known o modi y me abolism o chemo he apy d ugs, he eby al e ing d ug e ec i eness. Fo
example, En e ococcus aecalis inac i a es 5-FU, blun ing i s cy o oxic e ec [17]. P. gingi alis is also known o igge
d ug e lux pumps wi hin cance cells, educing in acellula d ug le els and leading o chemo esis ance [11].
5.2.2. Mic obiome Impac on Toxici y o Chemo he apy
Chemo he apy-induced o al mucosi is is agg a a ed by mic obiome dysbiosis, which esul s in an o e g ow h o
oppo unis ic pa hogens ha ex end in lamma ion and aise seconda y in ec ions [36].
Mic obiome modula ion p ocedu es like p ebio ics and p obio ics can mi iga e mucosi is and enhance chemo he apy
ole ance [37]. In addi ion, new in e en ions like mic obial enginee ing and die a y adjus men s ha e po en ial in
e adica ing bac e ia in ol ed in chemo esis ance.
6. Immuno he apy: he mic obiome as a p edic o o esponse
Immuno he apy & immune checkpoin inhibi o s (ICIs) agains PD-1/PD-L1 in pa icula , has e olu ionized HNSCC
ea men . Ye , he mic obiome is an impo an de e minan o esponse a es.
6.1. Mic obiome Composi ion and Immuno he apy Response
Pa ien s wi h a mo e di e se ichness o commensal bac e ia (Lac obacillus and Bi idobac e ium spp.) ha e g ea e
eac ions o PD-1 inhibi o s [7]. On he o he hand, immune e asion and ICIs esis ance is linked wi h p o-in lamma o y
species F. nuclea um and P. gingi alis [38].
6.2. Mic obiome-Media ed Immune Modula ion
Some bac e ial me aboli es, including sho -chain a y acids (SCFAs), modula e T-cell unc ion and an i- umo immune
esponses [39]. F. nuclea um also inhibi s cy o oxic CD8+ T-cell unc ion, weakening he e ec i eness o immune
checkpoin blockade [10].
6.3. Mic obiome-Immune The apy Syne gy
Mic obiome-di ec ed ea men s, such as ecal mic obio a ansplan a ion (FMT) and mic obiome he apeu ics, a e
being in es iga ed o augmen immuno he apy e ec i eness [17]. Clinical ials ha e shown ha pa ien s who ecei e
mic obiome-modula ing he apies in combina ion wi h ICIs ha e be e su i al a es.
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7. Mic obiome-based he apeu ic s a egies in HNSCC
As mo e e idence con e ges linking he dysbiosis o o al mic obiome wi h HNSCC disease p og ession and
chemo esis ance, scien is s a e en u ing o unde s and mic obiome-manipula ing he apeu ic app oaches o a be e
esponse in ea men . Se e al me hods such as p obio ics, p ebio ics, an ibio ics, bac e iophage he apy,
ansplan a ion o mic obio a, and enginee ing o he mic obiome ha e s epped o wa d as e icien adjunc s wi h
adi ional an icance he apies.
P obio ics and P ebio ics a e impo an in es o ing he balance o mic obes and enhancing immune esponse. The e
a e bene icial s ains o bac e ia like Lac obacillus and Bi idobac e ium, which ha e shown p omise in inhibi ing cance -
ela ed pa hogenic bac e ia. P obio ics educe in lamma ion, boos immuni y in he gu and he mou h, and enhance
o e all ea men ou comes [40]. P ebio ics like die a y ibe and polyphenols eed he abo e-men ioned bene icial
bac e ia and help inc ease he heal hy composi ion o he mic obiome [41]. Resea ch indica es ha he addi ion o
p obio ic supplemen a ion may alle ia e mucosi is induced by ea men and lowe chemo adio he apy complica ions
[12]. Selec i e An ibio ic The apy and Bac e iophage T ea men a e also being in es iga ed as p ecision-based me hods
o kill cance - ela ed bac e ia wi hou ha ming use ul mic obial communi ies. Pa hogenic gene a like Po phy omonas
gingi alis and Fusobac e ium nuclea um ha e been linked o umo g ow h and immune supp ession. I may be possible
o dec ease chemo esis ance and inc ease he e icacy o immuno he apy by a ge ing hese bac e ia wi h na ow-
spec um an ibio ics o bac e iophage he apy, which employs i uses o selec i ely des oy ha m ul bac e ia. Bu
selec ion mus be done cau iously o p e en des abilizing he en i e mic obiome and hus po en ially in e e ing wi h
immune unc ion and ea men e icacy [17].
Mic obio a T ansplan a ion has been in he spo ligh as a p omising app oach o maximize he immune en i onmen
o cance ea men . Fecal mic obio a ansplan a ion (FMT), whe e heal hy gu mic obio a a e ansplan ed o egain
mic obial homeos asis, was ound o be p omising in enhancing esponse o immune checkpoin inhibi o s in cance s
like melanoma. In conside a ion o he obus ela ionship be ween gu and o al mic obiomes, ansplan a ion o o al
mic obio a (OMT) has been p oposed o i s e icacy o al e HNSCC- ela ed umo -associa ed dysbiosis. Th ough his
measu e, i has been sugges ed, enhanced immuno he apy a es, dec ease in in lamma o y cy okines, and be e umo
mic oen i onmen can be enhanced.
Mic obiome Enginee ing and Me aboli e-Based The apies a e no el s a egies ha u ilize bac e ial al e a ions o
he apeu ic in e en ion. Scien is s a e in es iga ing he po en ial o gene ically enginee ed commensal bac e ia o
a ge an icance compounds di ec ly o he umo . Mo eo e , mic obial me aboli es, including sho -chain a y acids
(SCFAs) and polyamines, ha e been ecognized as c ucial egula o s o umo g ow h and immune esponses.
In gene al, inco po a ing mic obiome- a ge ed he apies in o HNSCC ea men egimens has he po en ial o ans o m
cance he apy. Reducing esis ance o ea men , s imula ing immune unc ion, and minimizing ad e se e ec s, hese
app oaches hold much p omise o cus omized cance he apy.
Ye , mo e clinical ials mus be conduc ed o demons a e he sa e y, e ec i eness, and long- e m consequences o
mic obiome-based ea men s. Wi h ad ancing insigh s in o he connec ion be ween he umo and mic obiome, he
use o mic obiome modula ion could become a undamen al aspec o p ecision oncology o HNSCC pa ien s.
8. Conclusion
Any o al o sys emic illness de elops based on he impo ance o o al mic obiomes. The in e ac i e ela ionship
be ween o al mic obiome unc ions as a signi ican indica o owa d de eloping mic obiome-based p ecise cance
he apy o HNSCC pa ien s. The ecogni ion o mic obial ea men esponses enables clinicians o de elop imp o ed
ea men in e en ions ha gene a e supe io pa ien esul s. Fu u e medical esea ch should dedica e i s e o s o
in eg a ed he apeu ic app oaches which ocus on o al mic obiome in e en ions h ough p obio ic ea men s,
mic obiome ansplan ed he apies, and bac e ial inhibi ion me hods in o s anda d HNSCC clinical ca e. Be e
knowledge abou hese in e ac ions will be i al o op imizing he apy e icacy while minimizing esis ance o ensu e
imp o ed su i al a es.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 26(02), 2555-2562
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Compliance wi h e hical s anda ds
Disclosu e o con lic o in e es
The au ho decla e ha he e is no po en ial con lic o in e es wi h espec o he au ho ship and/o publica ion o
his a icle.
Re e ences
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