Review

HPV and Cervical Cancer—Biology, Prevention,

and Treatment Updates
Emilia Włoszek 1, *, Kamila Krupa 1 , Eliza Skrok 1 , Michał Piotr Budzik 2 , Andrzej Deptała 2
and Anna Badowska-Kozakiewicz 2

1 Students’ Scientific Organization of Cancer Cell Biology, Department of Oncology Propaedeutics,

Medical University of Warsaw, 02-091 Warsaw, Poland; [Link]@[Link] (K.K.);
s085306@[Link] (E.S.)
2 Department of Oncology Propaedeutics, Medical University of Warsaw, 02-091 Warsaw, Poland;
[Link]@[Link] (M.P.B.); [Link]@[Link] (A.D.); abadowska@[Link] (A.B.-K.)
* Correspondence: [Link]@[Link]

Abstract: One of the most significant breakthroughs in cancer research has been the iden-
tification of persistent infection with certain human papillomaviruses (HPV) genotypes
as the cause of cervical cancer. Since then, a range of diagnostic and therapeutic meth-
ods has been developed based on this discovery. This article aims to describe the latest
updates in the biology, prevention, and treatment of HPV-related cervical cancer. The
current state of knowledge regarding vaccinations, diagnostic tests, and cervical cancer
therapies is presented. The latest WHO guidelines on vaccinations are presented, as well as
announcements of upcoming changes. The final part of the article summarizes promising
new diagnostic and treatment methods, as well as perspectives and the latest research
findings on self-administered diagnostic tests, the use of therapeutic vaccines, and circu-
lating cell-free DNA in diagnosis. Despite the significant progress made in recent years,
the strategy based on vaccination and testing remains the cornerstone in the fight against
HPV-related cervical cancer.

Keywords: human papillomavirus; HPV; cervical cancer; vaccination; screening;

systemic therapy

Received: 27 January 2025

Revised: 13 February 2025 1. Introduction
Accepted: 20 February 2025
Papillomaviruses are small, double-stranded DNA viruses that specifically infect
Published: 22 February 2025
squamous epithelia or cells capable of squamous maturation. These viruses are strictly
Citation: Włoszek, E.; Krupa, K.;
species-specific, meaning that human papillomaviruses (HPVs) exclusively infect humans.
Skrok, E.; Budzik, M.P.; Deptała, A.;
They exhibit remarkable tissue tropism, completing their infectious cycle only in fully
Badowska-Kozakiewicz, A. HPV and
Cervical Cancer—Biology, Prevention,
differentiated squamous epithelium. Over the past 25 years, one of the most significant
and Treatment Updates. Curr. Oncol. breakthroughs in cancer research has been the identification of persistent infection with cer-
2025, 32, 122. [Link] tain HPV genotypes as the cause of cervical cancer. Comprehensive virological, molecular,
10.3390/curroncol32030122 clinical, and epidemiological studies have provided definitive evidence that cervical cancer
Copyright: © 2025 by the authors. results from prolonged, unresolved infection by specific HPV genotypes. Consequently, it
Licensee MDPI, Basel, Switzerland. is now understood that cervical cancer is the outcome of a viral infection. This recognition
This article is an open access article highlights vaccination as a vital strategy for the primary prevention of cancers and other
distributed under the terms and
diseases associated with HPV. Considering the findings of the research conducted in recent
conditions of the Creative Commons
years, HPV infection may be a contributing factor in the development of many other types
Attribution (CC BY) license
([Link]
of cancer. The aim of this paper is to discuss the current state of knowledge about the HPV
licenses/by/4.0/). virus, present the latest discoveries in this field, and explore potential future possibilities

Curr. Oncol. 2025, 32, 122 [Link]

Curr. Oncol. 2025, 32, 122 2 of 22

related to diagnosis and treatment. PubMed and Google Scholar databases were used to
collect data for this review using the following phrases: HPV epidemiology, HPV classifica-
tion, HPV cycle, HPV pathogenesis, HPV screening, colposcopy, microbiota dysbiosis and
HPV, HPV vaccine, HPV infection, HPV related cancers, cervical cancer screening, cervical
cancer treatment, advanced cervical cancer, and HPV E6 E7.

2. Epidemiology
Chesson et al. estimated the lifetime probability of human papillomavirus (HPV)
infection in the United States before it was introduced to HPV vaccination. The analysis
revealed that over 80% of men and women would have HPV by age 45. Among individuals
with at least one opposite-sex partner, 85% of women and 91% of men were projected to con-
tract HPV during their lifetime [1]. The metanalysis from 2010, encompassing 194 studies,
including about one million women tested for cervical HPV infection, showed that the most
common types are HPV16, 18, 52, 31, 58, 39, 51, and 56, but the prevalence differs among
the regions. Sub-Saharan Africa had the highest prevalence (24.0%), especially Eastern
Africa (33.6%). The infection is more prevalent in poor nations than in industrialized ones,
according to the geographic distribution. However, regardless of development level, West
Asia (1.7%) exhibits the lowest prevalence, whereas Eastern Europe (21.4%) exhibits high
prevalence [2]. North America has the lowest genotypic diversity, while Asia displays
the highest [3]. Moreover, the latest meta-analysis showed that genital HPV infection
prevalence is high in men over the age of 15. Globally, nearly one in three men are infected
with HPV of any type, and approximately one in five men carry one or more high-risk (HR)
HPV types [4].

3. Classification of HPV Viruses

The classification of the HPV viruses is based on differences in DNA sequence. There
are five genera of HPV: alpha, beta, gamma, mu, and nu, which are divided into HR-HPV
and low-risk HPV (LR-HPV) subtypes [5]. Currently, there are at least 448 types of HPV,
15 of which have been classified as carcinogenic: HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56,
58, 59, 68, 73, and 82 [6,7]. Types 26, 53, and 66 are considered potentially carcinogenic [7].
HPV16 and HPV18 exhibit the highest oncogenic potential; nevertheless, regional genetic
diversity influences their pathogenicity [8]. Based on comparisons of the HPV16 long
control region (LCR) sequences, we can distinguish five groups: European (E), Asian (As),
Asian-American (AA), African 1 (Af-1), and African 2 (Af-2) [3].

4. Risk Factors
While barrier contraception methods, e.g. condoms, are successful in minimizing the
transmission of numerous sexually transmitted infections, they are not entirely effective
against HPV, as the virus can also be transferred via skin-to-skin contact or by contact
between infected fingers and genitalia [9]. In addition, C. trachomatis may increase the risk
of HPV infection and promote virus persistence [10,11]. Other risk factors include gender,
young age, and the number of sexual partners [9,12]. Intercourse with a new sexual partner
carries an increased risk of viral infection and, potentially, cancer development [13,14].
Women are more susceptible to infection with the HPV. The frequency of HPV detec-
tion occurs in two peaks. The most infected are girls in puberty and women under 20 years
of age. Detection of HPV, especially LR-HPV, also concerns elderly women over 55 years
of age, which may be related to the persistence or reactivation of a previously acquired
infection, rather than new or recent infections [15,16]. An increasing number of full-term
pregnancies is associated with a higher risk of invasive cervical carcinoma and chronic
Curr. Oncol. 2025, 32, 122 3 of 22

HPV infection. This association may be due to pregnancy-induced immunosuppression,

which may favor the HPV infection or enhance its carcinogenic potential [17,18].
Children may become infected with HPV through contact between a parent’s wart,
present on the hand, and the child’s skin while changing a diaper or cleaning the anogenital
area [19,20]. There is also a risk of infection with the virus in the perinatal period, because
the same type of HPV has been detected in both mothers and newborns [21]. If the mother
has a genital HPV infection, the fetus can contract the virus through micro-tears in the fetal
membranes or the placenta [19]. Since HPVs do not induce viraemia, it is unlikely that the
virus is spread through breast milk [22].
New studies show that tobacco smoking promotes the progression of HR-HPV-
induced lesions to precancerous and squamous cell carcinomas of the head and neck,
cervix, anus, and penis [23–25]. Compounds present in cigarette smoke, of which at least 60
are oncogenic in humans, may contribute to increased expression of the virus in cells [26].
Whether oral hormonal contraception increases the progression of HPV infection remains
controversial, and further analysis is therefore necessary [27]. The latest studies exhibit
that certain conditions, such as diabetes, prediabetes, and immunosuppression, predispose
individuals to HPV infection [25,28]. The persistence of the HPV, especially high-risk
types, may be also seen in people with defective immune responses, such as those who
are HIV-positive [29,30]. Additionally, HPV is a contributing factor in the pathogenesis of
vaginal intraepithelial neoplasia in diethylstilbestrol (DES)-exposed patients [31].

5. Pathogenesis and Symptoms of Infection

Undifferentiated basal epithelial cells are infected by the HPV. Nevertheless, access
to the lowest cell layer is restricted by the remaining epithelial layers made by fully
differentiated cells [32]. The infection occurs through microinjuries that expose deeper
layers of the epithelium, allowing the binding of the virion L1 protein to heparin sulfate
proteoglycans. In the next step, the capsid changes conformation by cyclophilin B and loses
affinity for the primary receptor [33,34]. The N-terminus of the L2 protein is exposed, prone
to furin-related proteases. Endosomal escape and infection both require protein cleavage,
so lack of interaction with furin prevents escape from the endocytic compartment [35–37].
After many hours of asynchronous internalization of the capsid with the plasma
membrane, endocytosis occurs, which is dependent on actin instead of clathrins, lipid
rafts, dynamin, or caveolin [31,32]. Virions are transported in endosomes with an acidic
environment, where they undergo subsequent structural changes. The L1 protein is directed
to lysosomes for degradation, whereas the L2 protein enables the escape of the genome/L2
complex to late endosomal compartments by binding to nexin 17, a sorting protein [32,38].
Moreover, the C-terminus of the L2 protein enables the association with microtubule
dynein, which allows the transport of the complex to the nucleus (Figure 1) [39]. Initially,
transcription of the E1 and E2 proteins occurs. During the S phase of virus genetic material
replication, the E2 protein stabilizes its interaction with DNA, while the E1 acts as an ATP-
dependent DNA helicase [40–42]. The HPV virus does not have the remaining enzymes
necessary for replication, so it uses the host’s enzymes for this purpose. The E6 and
E7 proteins can alter the cellular environment in terminally differentiated or growth-
arrested cells, which leads to viral genome amplification [32]. As a result of degradation of
the pRb protein, the E2F protein is continuously active and binds to DNA transcription
factors, leading to the expression of cyclins and other proteins of the cycle. Finally, the
virus is assembled in terminally differentiated keratinocytes, where access to oxygen is
possible. Disulfide bridges are formed between the L1 proteins, ensuring condensation and
stabilization of the capsid [43]. The exit from the cell is mediated by the E4 protein, which
binds to cytokeratin filaments [44,45].
 and stabilization of the capsid [43]. The exit from the cell is mediated by the E4 protein,
Curr. Oncol. 2025, 32, 122 which binds to cytokeratin filaments [44,45]. 4 of 22

Figure 1. Pathogenesis of HPV infection. Abbreviations: HSPG–heparin sulfate proteoglycans. Orig-

Figure 1. Pathogenesis of HPV infection. Abbreviations: HSPG–heparin sulfate proteoglycans.
inal
Original work
work based
basedon on
[46].
[46]. The graphic shows the process of Human Papillomavirus (HPV)
infection in epithelial cells. The virus enters the deepest layer of the epithelium as a result of tissue
damage,The whichgraphic
allowsshows the process
it to interact of Human
with the Papillomavirus
cells of the basal layer of the(HPV) infection
epidermis. in epithe-
In the next
lial cells. The virus enters the deepest layer of the epithelium as a result
steps (shown in the diagram), HPV binds to heparan sulfate proteoglycan (HSPG) on the cell surface of tissue damage,
(1),which allows itconformational
which induces to interact with the cells
changes of theof the basal
capsid layer ofofthe
and exposure theepidermis.
N-terminusIn the L2
of the next
steps(2).
protein (shown
This isin the diagram),
followed HPVofbinds
by cleavage L2 by to heparan
furin (3) andsulfate proteoglycan
actin-dependent (HSPG)ofon
endocytosis thethe
virus
cell(4). After internalization,
surface (1), which inducesthe capsid including L1 protein
conformational changes areofdegraded
the capsid(5), and
and the L2-genome
exposure of the
complex is transported
N-terminus to the
of the L2 cell nucleus
protein with
(2). This is help of theby
followed dynein complex
cleavage of L2(6).by
Infurin
the final
(3) phase of
and actin-
thedependent
replication cycle, the virusofisthe
endocytosis assembled in After
virus (4). terminally differentiatedthe
internalization, keratinocytes and released
capsid including L1 pro-
into the environment.
tein are degraded (5), and the L2-genome complex is transported to the cell nucleus with
help of the dynein complex (6). In the final phase of the replication cycle, the virus is as-
Symptoms of primary infection are not noticeable early, as most HPV infections are
sembled in terminally differentiated keratinocytes and released into the environment.
transient. They resolve after 12–18 months in the case of high-risk HPV infections or after
Symptoms of primary infection are not noticeable early, as most HPV infections are
4–9 months in the case of low-risk HPV infections [47]. The cervicovaginal microbiome
transient.
(CVM) playsThey resolve after
a significant role12–18
in themonths in the case
elimination of the of virus
high-risk
andHPV infections
the risk or after
of cervical
4–9 months in the case of low-risk HPV infections [47]. The cervicovaginal
intraepithelial neoplasia 2 or higher (CIN 2/CIN 2+) [48]. A dominance in Lactobacillus microbiome
(CVM)
spp. in CVMplays a significant
is associated withrole in the elimination
protective role againstofHPVthe and
virus and the risk
decreased risk ofof HR-HPV-
cervical in-
traepithelial neoplasia 2 or higher (CIN 2/CIN 2+) [48]. A dominance in
induced CIN lesions [49,50]. In addition, a decreased population of some bacteria leads Lactobacillus spp.
in CVM
to an is associated
increased number of with protective
bacteria role against
associated with theHPV and decreased
persistence of HR-HPV risk of HR-HPV-
infections
and precancerous lesions, such as Gardnerella spp. (Gardnerella vaginalis), Mobiluncusleads
induced CIN lesions [49,50]. In addition, a decreased population of some bacteria spp., to
an increased
Prevotella number amnii,
spp., Sneathia of bacteria associated spp.,
Porphyromonas with the persistence of HR-HPV
Peptostreptococcus spp., andinfections
Atopobium and
precancerous lesions, such as Gardnerella spp. (Gardnerella vaginalis), Mobiluncus
vaginae [51]. The findings highlight a significant interplay between vaginal microbiota and spp.,
Prevotella
HPV, spp.,that
suggesting Sneathia amnii,
microbial Porphyromonas
dysbiosis spp.,as
could serve Peptostreptococcus
a diagnostic markerspp.,orand Atopobium
therapeutic
target. Monitoring the presence of Gardnerella spp. in CMV may allow predicting viral
persistence and future cancer risk due to its immunosuppressive properties [3,48]. Specific
Gardnerella spp. produce sialidase (neuraminidase), encoded by nanH2 and nanH3 genes,
Curr. Oncol. 2025, 32, 122 5 of 22

which degrade protective vaginal mucosa, detach epithelial cells, and promote biofilm
formation [52]. In Novak et al. study women who continue to have cervical HPV16
infection after a year or bacterial vaginosis have higher baseline levels of the nanH3
gene [52]. Furthermore, the amount of Lactobacillus spp. may become the prognostic tool of
HPV elimination. However, larger prospective studies are needed to validate findings, and
applications of innovative microbiome modulation strategies [48,49,51].
The most important symptoms that may indicate an HPV infection include skin warts,
condyloma acuminata, and recurrent respiratory papillomatosis. Cutaneous warts most
often caused by beta and gamma HPV (HPV4, HPV65) are often found in children and
young adults, and the peak detection rate reaches 10–14 years of age [3,53]. They are more
often observed in males or immunocompromised individuals. Infection most often occurs
through skin-to-skin contact. Most of the lesions regress spontaneously within 2 years.
In immunocompromised individuals, the risk of developing squamous cell carcinoma
is higher [53,54]. HPV6 and 11 are responsible for 90% of condyloma acuminata cases
in the anogenital region, on the tongue or lips [55]. The time between the infection and
the development of lesions is 11–12 months in men and 5–6 months in women [56]. The
possible reason for the duration differences between the development of lesions after HPV
infection are immune response, and also anatomical and biological differences, although
more focus should be paid to specify the significant ones. Monsonego et al. showed
that sex steroid hormones, especially progesterone, may act indirectly on HPV-infected
epithelial cells and be implicated as co-factors in HPV-related cervical neoplasia [57].
Ogawa et al. showed that the estrogen/G protein-coupled receptor 30 (GPR30) signaling
is involved in proliferation of adenocarcinoma and normal endocervical columnar cells.
Additionally, estrogen induced genomic instability, by increasing the number of DNA
double strand breaks, leading to carcinogenesis of cervical adenocarcinoma [58]. The
lesions appear as flat or small nodules. On moist mucosal surfaces, they may manifest
as white or pink, soft growths, while keratinized lesions are characteristic of epithelia
with a thick stratum corneum [59]. As a result of HPV16 or HPV18 infection, they may be
classified as Bowenoid papulosis, showing condylomatous features with intraepithelial
neoplasia. If there is a risk of transformation into cancer, it is possible to remove them during
surgery [60].
Recurrent respiratory papillomatosis (RRP) is a benign condition that can develop after
an HPV6 or HPV11 infection. It affects the larynx, trachea, pharynx, nasopharynx, nose,
oral cavity, and lung parenchyma. It manifests itself with hoarseness, but there is a risk
of blocking the airways by the enlargement of the primary cauliflower-like lesion [53,61].
The progressive dysphonia is also an initial symptom in adults [62]. There is a distinction
between JoRRP (Juvenile-onset RRP), which is most often acquired perinatally, and AoRRP
(Adult-onset RRP), which is associated with oral sex. The first one is very common in
Sub-Saharan Africa, while the second one in Europe and South America [53].

6. HPV-Related Cancers: Pathogenesis and Epidemiology

The most significant role in the pathogenesis of neoplastic changes resulting from HPV
infections is played by the proteins E5, E6, and E7. The E5 protein, present in all types of HR-
HPV, except for Betapapillomaviruses, promotes cancer progression by binding to platelet
growth factor receptors (PDGFR) and epidermal growth factor receptors (EGFR) [63]. The
E6 protein plays a key role in inhibiting the regulation of the cell cycle, as it inactivates the
p53 protein. By stimulating the Wnt/β-catenin and Notch pathways, it disrupts normal cell
signaling. It also promotes cell immortality by activating telomerase. The E7 protein inhibits
the action of pRb, p107, p130. As a result, the E2F factor is activated, which promotes the
transition from G1 to S phase (Figure 2) [63,64]. Moreover, in oncogenic HPV types, it binds
 disrupts normal cell signaling. It also promotes cell immortality by activating telomerase.
The E7 protein inhibits the action of pRb, p107, p130. As a result, the E2F factor is acti-
vated, which promotes the transition from G1 to S phase (Figure 2) [63,64]. Moreover, in
Curr. Oncol. 2025, 32, 122 6 of 22
oncogenic HPV types, it binds to the non-receptor protein tyrosine phosphatase PTPN14,
leading to its degradation, which results in inhibition of keratinocyte differentiation and
their
to the immortality
non-receptor [65]. tyrosine
protein Both proteins may activate
phosphatase PTPN14, the PI3K/AKT/mTOR
leading and JAK/STAT
to its degradation, which
signaling pathways, which play a role in the pathogenesis of
results in inhibition of keratinocyte differentiation and their immortality [65]. Both cancer. Inproteins
particular,
mayJAK/STAT plays
activate the an important roleand
PI3K/AKT/mTOR in the development
JAK/STAT of cervical
signaling cancer
pathways, [9,66,67].
which playThese
a
role in the pathogenesis of cancer. In particular, JAK/STAT plays an important role in thesup-
proteins also participate in the inhibition of the immune response. The E5 protein
presses interferon
development of cervical(IFN)
cancersignaling
[9,66,67].pathway and retains
These proteins MHC-I molecules
also participate in the ER
in the inhibition ofand
the immune response. The E5 protein suppresses interferon (IFN) signaling pathway and a
Golgi Apparatus. The E6 protein has the ability to reduce antigen presentation through
transporter
retains associatedin
MHC-I molecules with
the antigen processing
ER and Golgi complex
Apparatus. The(TAP) interference.
E6 protein has theIn turn, E7
ability
increases the population of Treg lymphocytes, thereby reducing cytotoxic
to reduce antigen presentation through a transporter associated with antigen processing T, and inhibits
pyroptosis.
complex (TAP) Moreover,
[Link] In proteins cause up-regulation
turn, E7 increases the populationof immune
of Treg checkpoint
lymphocytes, mole-
cules such as PD-L1 [68].
thereby reducing cytotoxic T, and inhibits pyroptosis. Moreover, both proteins cause
up-regulation of immune checkpoint molecules such as PD-L1 [68].

Figure 2. Pathogenesis
Figure of HPV-related
2. Pathogenesis cervical
of HPV-related cancer.
cervical Abbreviations:
cancer. CIN–cervical
Abbreviations: intraepithelial
CIN–cervical intraepithelial
neoplasia. The
neoplasia. graphic shows the mechanism leading from human papillomavirus (HPV) infection to
the progression to cervical cancer. After infection of the epithelium, the virus can persist as a chronic
infection, The
leading to pre-cancerous
graphic shows thechanges (CIN—cervical
mechanism intraepithelial
leading from neoplasia) and then
human papillomavirus cervical
(HPV) infec-
cancer. The oncogenic mechanism of HPV proteins E6 and E7 is shown in the upper right corner.
tion to the progression to cervical cancer. After infection of the epithelium, the virus can
The E6 protein inhibits the action of the tumor suppressor p53 and activates telomerase, supporting
persist as a chronic infection, leading to pre-cancerous changes (CIN—cervical intraepi-
uncontrolled cell proliferation. Additionally, it stimulates the Wnt/beta-catenin pathway and the
thelial neoplasia) and then cervical cancer. The oncogenic mechanism of HPV proteins E6
Notch pathway, disrupting cell signaling. On the other hand, E7 deactivates proteins regulating
andcycle
the cell E7 is(pRB,
shown in p130).
p107, the upper right corner.
Deactivation of pRB The E6 protein
protein leads toinhibits the activation
continuous action of the tumor
of E2F,
suppressor
dysregulation p53
of the celland
cycleactivates
promotingtelomerase,
the transition supporting uncontrolled
from G1 to S phase, cell proliferation.
and uncontrolled division
of epithelial cells. Moreover, the graphic shows the impact of vaginal microbiota dysbiosis on HPV
infection. A reduction in the number of protective Lactobacillus spp. and an increase in the population
of Gardnerella vaginalis may promote chronic HPV infection and the progression to cancer. The graphic
also shows the most common oncogenic HPV types associated with cervical cancer: HPV16, HPV18,
HPV31, HPV52, and HPV58.
Curr. Oncol. 2025, 32, 122 7 of 22

The HPV is associated with 4.5% of all cancers, 8.6% of cancers in women, and 0.8%
in men [69]. According to GLOBOCAN data, in 2022, cervical cancer (CC) occurred
at a rate of 19.3 per 100,000 women and was the fourth most common cancer in both
incidence and mortality in women, with an estimated 660,000 new cases and 350,000 deaths
worldwide [6]. The risk of acquiring cervical cancer is 75.4 times higher for women with
chronic HR-HPV infections than for women who are HPV-negative, according to a 16-year
follow-up study [70]. HPV16 is the most common subtype of the virus in CC globally.
The next positions are occupied by HPV18, HPV52, HPV31, and HPV58 [71]. Chronic
HR-HPV infection causes cervical illness, which in turn causes cervical cancer. Cervical
lesions originate in the transformation zone (TZ), which is situated at the junction between
the ectocervix and the endocervix. Low-grade squamous intraepithelial lesions (LSIL)
are represented by CIN 1 and high-grade squamous intraepithelial lesions (HSIL) are
represented by CIN 2 and CIN 3. The replication activity decreases as the grade of lesion
increases [68].
Cervical cancer is not the only cancer associated with HPV infection. Vulvar cancer
and vaginal cancer are associated with HPV in 70% and 75%, respectively [72]. Moreover,
HPV viruses cause about 26–30% of head and neck cancers, where the incidence of HPV-
related oropharyngeal squamous cell carcinoma (OSCCC) is about 30% (data from 2020)
and is constantly increasing, especially in developed countries [73]. In the last two decades
in some European countries, the incidence has increased significantly [30,74]. Women have
a higher incidence of anal cancer and precancerous anal lesions than men, and 90% of
these lesions are related to HPV16, 18, and 33 [72,75]. The incidence is particularly high
in men who have sex with men (MSM), especially those with HIV [76,77]. Penile cancer
is related to HPV in 60% of cases [72]. Moreover, this virus can be detected in 79.8% of
cases of penile intraepithelial neoplasia (PeIN) and 90% of genital warts cases. The most
frequently documented subtype was HPV16 [53]. It has been demonstrated that HR-HPV
found in benign prostatic tissues immortalizes prostate cells, which could be connected
to the gradual transformation of the prostate gland from a benign neoplasm to prostate
cancer [78,79].

7. World Health Organization Guidelines—HPV Vaccine

Currently there are six licensed HPV vaccines (Table 1). In 2020, the World Health
Organization (WHO) updated its position on human papillomavirus (HPV) vaccines,
introducing new recommendations that included the option of a single-dose schedule [80].
This approach, endorsed by the WHO’s independent advisory group SAGE in April
2020 [81], offers efficacy and protection comparable to the traditional two- or three-dose
regimen. The update comes amidst alarming global declines in HPV vaccination rates.
Between 2019 and 2021, the proportion of girls receiving the first dose of the vaccine
dropped from 25% to 15%, leaving an additional 3.5 million girls unvaccinated in 2021
compared to 2019 [82].

Table 1. WHO-licensed HPV vaccines 2024 [83].

Brand Name [83] Valency Target–HPV Types

Cervarix bivalent 16, 18
Cecolin bivalent 16, 18
Walrinvax bivalent 16, 18
Gardasil quadrivalent 16, 18
Cervavax quadrivalent 16, 18, 6, 11
Gardasil9 nonvalent 16, 18, 31, 33, 45, 52, 58, 6, 11
Curr. Oncol. 2025, 32, 122 8 of 22

The revised guidelines aim to enhance vaccine accessibility by simplifying vaccination

logistics, reducing the costs and challenges associated with follow-up appointments, and
enabling countries to vaccinate a larger number of girls. The WHO emphasizes the urgent
need to strengthen HPV vaccination programs, implement these updated schedules swiftly,
and reverse recent declines in coverage [82].
In 2022, further evidence confirmed that a single HPV vaccine dose could provide
strong protection against persistent HPV infection [84]. This prompted the WHO to recom-
mend a flexible approach, allowing countries to adopt either a one- or two-dose schedule
for key target groups:
• Girls aged 9–14 years: one or two doses.
• Young women aged 15–20 years: one or two doses.
• Women over 21 years: two doses spaced 6 months apart.
Special guidelines prioritize individuals who are immunocompromised or living with
HIV. These individuals should receive at least two doses and, when feasible, three doses
for optimal protection [85].
The WHO continues to advocate for vaccinating girls aged 9–14 years during early
adolescence, ideally before sexual activity begins. Focusing on girls not only directly
prevents cervical cancer but also offers herd immunity to boys when coverage is high. This
strategy is more cost-effective than vaccinating both sexes, although some regions choose
to include boys in their programs [82].
In low- and middle-income countries (LMICs), school-based vaccination programs
have proven particularly effective, achieving higher coverage rates than healthcare facility-
based efforts. Countries that have achieved widespread HPV vaccination among adolescent
girls have documented significant decreases in HPV prevalence, cervical precancers, and
invasive cervical cancers. These successes underscore the critical role of robust vaccination
programs in combating HPV-related diseases globally [82].

8. World Health Organization—HPV Vaccine News 2024

In October 2024, the World Health Organization (WHO) announced the prequalifi-
cation of Cecolin as the fourth human papillomavirus (HPV) vaccine approved for use
in a single-dose schedule [86]. This decision was supported by new data demonstrating
that Cecolin meets the criteria established in the WHO’s 2020 guidelines for alternative,
off-label single-dose HPV vaccination. This milestone is expected to enhance the global
supply of HPV vaccines, making it possible to vaccinate more girls and reduce the burden
of cervical cancer.
The Cecolin HPV vaccine, a domestic bivalent vaccine targeting HPV types 16 and
18, was introduced in China in 2020 at a lower price than imported alternatives [87].
Clinical trials have demonstrated its safety and immunogenicity, with non-inferiority to
Gardasil in a two-dose schedule [88]. A phase 2 trial of a nonavalent version, Cecolin
9, showed high seroconversion rates and good tolerability in women aged 18–45 [89]. A
network meta-analysis comparing HPV vaccines found that Cecolin was most effective
against HPV 18 persistent infection, with 98% efficacy [90]. However, public perception
varies, with women in economically developed areas preferring imported vaccines due to
concerns about effectiveness and quality [87]. Increasing awareness and education about
the domestic vaccine, particularly in underdeveloped areas, could help prevent cervical
cancer and improve vaccine uptake [87].
Curr. Oncol. 2025, 32, 122 9 of 22

In addition, on 2 August 2024, the WHO prequalified a fifth HPV vaccine, Walrinvax,
for global use. This vaccine is approved with a two-dose schedule, further strengthening
the supply of HPV vaccines and expanding access for girls in need of protection. A
study on this bivalent HPV16/18 vaccine demonstrated non-inferior immune responses
in adolescent girls compared to young women, with persistent antibody levels up to
36 months post-vaccination [91]. While Walrinvax is not currently recommended for
single-dose use, additional research may determine its suitability for this approach in
the future.
These developments represent significant progress in efforts to ensure sustainable HPV
vaccine availability worldwide, ultimately supporting expanded vaccination programs to
prevent cervical cancer on a larger scale.

9. The HPV Vaccination Strategy: The Example of Poland

The universal HPV vaccination program in Poland implements the assumptions and
goals of the National Oncology Strategy for 2020–2030. It supplements the free Vaccination
Program for children and adolescents with a new scope of protection against diseases
caused by HPV. The vaccines available under the program are 2-valent Cervarix and
9-valent Gardasil 9. As of 1 September 2024, free-of-charge vaccinations under the universal
HPV vaccination program are available for children from the age of 9 to the age of 14.
Vaccinations are administered in two doses. The interval between these doses in the
program is from 6 to 12 months [92]. Vaccination guidelines are aligned with the WHO
recommendations (Table 2).

Table 2. Vaccination guidelines in Poland, 2024 [93].

Age at the time of 4-valent vaccine

2-valent vaccine
commencement of vaccination 9-valent vaccine
2-dose regimen 2-dose regimen
second dose 5 to 13 months second dose 5 to 13 months
after the first dose after the first dose
9–14 years old
if the second dose of vaccine is administered earlier than
5 months after the first dose, administer the third dose
3-dose regimen 3-dose regimen
15 years old and older
(0, 1, 6 months) (0, 2, 6 months)

This marks a significant shift from the previous system where HPV vaccines were
recommended but not publicly funded [94]. The first program launched in 2023. Prior to
this program, HPV vaccination rates were low, with only 16% of adolescents reporting being
vaccinated [95]. A study conducted shortly after the program’s launch found that 51.3%
of adults were aware of the free vaccination program, with television being the primary
source of information [96]. The same study revealed that 63.3% of respondents were
willing to vaccinate their children against HPV. Factors associated with higher awareness
and willingness to vaccinate included female gender, higher education, and living in
large cities [96]. These findings highlight the importance of education and accessibility in
improving HPV vaccination rates in Poland.

10. Self-Sampling for HPV Testing

Cervical cancer can also be prevented through screening that detects precancerous
changes in the cervix, allowing for their treatment before they develop into cancer. In
the USA, women’s health professionals usually run a combination of Pap and HPV tests.
But, the new self-collection methods that have been approved can help women collect
Curr. Oncol. 2025, 32, 122 10 of 22

their samples by themselves in a range of healthcare settings, which may include pri-
mary care, mobile health clinics, etc. This development offers a great opportunity to
improve access and provide women with a more acceptable option to keep up with regular
screenings [97].
With HPV self-sampling, there is no need for a cervical exam. It collects vagi-
nal material via swabs, tampons, or brushes, which are analyzed for high-risk HPV
strains [98]. Evidence from randomized trials has shown that HPV testing is a more
effective screening method for cervical cancer than cytology [99]. Recent studies in-
dicate that self-collected vaginal samples for high-risk HPV testing are as sensitive as
cytologic examination of clinician-collected cervical samples. The former process is, how-
ever, less specific [98]. Plus, studies from randomized trials conducted internationally
show that sending out self-sampling kits increases participation in screening among
under-screened women as compared to clinician-collected samples [100]. Even so, some
women prefer clinician-collected samples because they are concerned about their abil-
ity to collect a reliable sample on their own [101]. Right now, we need more research
to understand how this affects screening frequency and if it causes any social harm or
adverse outcomes.

11. Screening Tests in the Diagnosis of HPV Infections

Recent studies on HPV screening in Poland reveal important insights into cervical
cancer prevention. Type-specific HPV DNA screening should focus on types 16, 18, and
45 [102,103]. A large-scale study using liquid-based cytology, HPV testing, and p16/Ki67
dual-staining demonstrated reporting rates consistent with international standards, indi-
cating the potential effectiveness of private-based screening models [104]. Self-reported
participation in cervical cancer screening has improved significantly, with 86.7% of Polish
women aged ≥15 years declaring they had undergone a Pap test by 2019. However, dispar-
ities in screening rates persist across age groups, education levels, urbanization, incomes,
and regions, highlighting the need for targeted interventions to address low participation
in specific demographics [105].
The free cytology program in Poland was launched 1 November 2023. It covers women
aged 25 to 64. The main goal is to reduce the number of women who get sick and die from
cervical cancer. A woman can have a cytology if she has not had one in the last three years.
She can also have a test after a year if she has risk factors such as HIV infection or HPV
or is taking immunosuppressive drugs. Woman can have a test under the program free of
charge if they are entitled to healthcare services [106].

12. The Role of Colposcopy in Cervical Cancer Screening—New Polish

Recommendations
Recent studies have examined the role of HPV testing and colposcopy in cervical
cancer screening. HPV testing has shown higher sensitivity than colposcopy in detecting
cervical intraepithelial neoplasia (CIN), while colposcopy demonstrates better specificity.
Combining HPV testing and colposcopy appears to be the most effective method for CIN
detection [107].
The 2020 recommendations of the Polish Society of Gynecologists and Obstetricians,
along with the Polish Society of Colposcopy and Cervical Pathophysiology, present an
updated approach to colposcopic terminology in Poland. These guidelines were devel-
oped based on the 2011 nomenclature created by the International Federation for Cervical
Pathology and Colposcopy (IFCPC) and seek to standardize practices and maximize clarity,
comparability, and global harmonization.
Curr. Oncol. 2025, 32, 122 11 of 22

Colposcopy is an integral part of cervical cancer screening programs worldwide,

having a particular role in the detection of HSIL and cervical cancer. These include the HPV-
dependent model of screening for secondary cervical cancer and terminological advances
from the LAST (Lower Anogenital Squamous Terminology) project.
Notably, the 2020 colposcopy terminology updates suggest the addition of the terms
“adequate” or “inadequate colposcopy,” replacing “satisfactory” or “unsatisfactory col-
poscopy,” which were used previously [108]. This shift highlights the diagnostic utility
of the exam rather than simply the visibility of the structures. Furthermore, additional
diagnostic features have been added to aid in recognizing colposcopic lesions. For ex-
ample, the “sign of the inner border” means a sharp boundary between the narrow
and wide whitening area, whereas the “ridge sign” indicates a transparent, elevated
folding in the transition zone. These updates enhance the prediction and detection
of HSIL.
The guidelines also refine the classification of colposcopic findings. Whether the
examination is adequate will depend on if it allows for diagnostic assessment. It is in-
adequate if it is hindered by factors such as inflammation, bleeding, or scarring. The
squamocolumnar junction (SCJ) is graded as fully visible, partially visible, or not visible.
The scientific name of these cervix regions is the transformation zone, and it is categorized
into three types: Type 1 (entire visible), Type 2 (partially visible but achievable), and Type
3 (not fully visible) [108]. Colposcopic findings that can be normal are mature squamous
epithelium, ectopia, and Nabothian cysts, as well as openings of the glands. Abnormal
findings are categorized as either minor changes consisting of thin acetowhitening and
fine mosaic patterns or major changes consisting of dense acetowhitening, coarse mosaics,
and punctation. Lugol’s iodine staining, previously fitted into the minor finding cate-
gory, has now been categorized as a nonspecific change because of its predictive value
for HSIL.
These recommendations go further to incorporate clinical and legal implications,
highlighting the importance of the standardization of terms in order to achieve accuracy,
ensuring consistency from cytology to histology and colposcopy. It has been brought out
that accurate documentation will reduce medical–legal risks and improve communication
among clinicians [108].

13. Treatment of HPV-Related Cervical Cancer

Depending on the cervical cancer stage at the time of diagnosis, the primary treat-
ment options with curative intent are surgery, chemoradiation, and a combination [109].
The presence of a cancer subtype (Squamous cell carcinoma (SCC), adenocarcinoma (AC),
adenosquamous carcinoma (ASC)) or HPV infection does not exclude any treatment op-
tion [109]. Three groups were distinguished to describe clinical management and will be
used to describe the latest updates in treatment, relating to Féderation Internationale de
Gynécologie et d’Obstétrique (FIGO) staging:
1. Early-Stage Cervical Cancer (FIGO IA-IIA)
2. Locally Advanced Cervical Cancer (LACC) (FIGO IIB–IVA, extending to the pelvic
side wall or adjacent organs)
3. Recurrent or Metastatic Cervical Cancer (FIGO IVB, any T any N, M+) [109–111].
The summary of treatment information is presented in Table 3.
Curr. Oncol. 2025, 32, 122 12 of 22

Table 3. Treatment of HPV-related cervical cancer updates.

FIGO Stage Guidelines New Options Additional Information References

FIGO IA Trachelectomy [111]
-laparoscopy or
robot-assisted surgery
cannot be regarded as
the preferred treatment
Radical/simple in comparison with
FIGO IB-IIA [111–118]
hysterectomy open surgery
-radiotherapy could be
safer than surgery for
postmenopausal
patients
-addition of
Platinum-derived induction -exploration of
chemotherapy and chemotherapy durvalumab use in
FIGO IIB-IVA concomitant external -addition of patients with high [109,112,119–128]
radiation therapy followed pembrolizumab to tumoral PD-L1
by brachytherapy the conventional expression
chemoradiotherapy
-pembrolizumab
combined with
Palliative
chemotherapy
chemo/chemoradiotherapy
(+/−bevacizumab) -second-line therapy
(combination of [109,112,115,128–
FIGO IVB -addition of choice depends on
platinum-based 131]
atezolizumab to a tumor characteristics
chemotherapy)
standard
Second-line therapy
bevacizumab plus
platinum regimen

13.1. Early-Stage Cervical Cancer (FIGO IA–IIA)

The treatment of choice in this stage is surgery, most commonly radical hysterectomy
combined with systematic pelvic lymphadenectomy with or without sentinel lymph node
(SLN) [112]. SLN dissection should be considered in FIGO stage I patients with tumors of
≤4 cm only in highly specialized centers. It is performed by injecting a tracer directly into
the cervix and using blue dye, technetium radiocolloid, or fluorescent indocyanine green.
Moreover, SLN should be detected on both sides. [111]. Microinvasive cervical cancer
(stage IA1) without lymphovascular space invasion (LVSI) can be treated with preservation
of fertility by conization or simple trachelectomy [111]. In the 2020 update in the clinical
guidelines, ESMO stated the fact that radical hysterectomy performed by laparoscopy
or robot-assisted surgery cannot be regarded as the preferred treatment in comparison
with open surgery [111,113,114]. In the ESGO2023 guidelines, radical hysterectomy in the
form of minimally invasive surgery may be considered only in low-risk tumors (<2 cm
and free margins after conization) and in high-volume centers only with the patient’s
consent [115]. The possibility of ovarian preservation should be considered, especially in
young women with HPV-related cervical cancer, but it is not recommended in cases of HPV-
independent adenocarcinomas [112]. If the ovaries are preserved, opportunistic bilateral
salpingectomy or exclusive radio-chemotherapy should be added to the treatment [115].
When we consider de-escalation from radical to simple hysterectomy in cervical cancer
tumors ≤2 cm, with the possible benefits and risks, we should point out that recent studies
confirmed that simple hysterectomy is comparable to radical in terms of the 3-year incidence
of pelvic recurrence [116–118]. In contrast to the previously mentioned recommendations,
Curr. Oncol. 2025, 32, 122 13 of 22

the 20-year randomized study showed that there was no advantage to surgery compared
to radiation in treatment for early-stage cervical carcinoma in terms of survival, and the
treatment should be chosen by considering clinical factors such as menopausal status and
comorbidities. Nevertheless, for histological-type adenocarcinoma, surgery was confirmed
as a better choice [132]. Expert opinions suggest that for postmenopausal patients with
comorbidities, radical radiotherapy could be a safer option in cases of FIGO I-II, but there
is no strong evidence [110].

13.2. Locally Advanced Cervical Cancer–LACC (FIGO IIB–IVA)

For many years, based on randomized phase III trials, the gold standard for
treating LACC was invariably platinum-derived (cisplatin alone [preferred] or cis-
platin/fluorouracil) chemotherapy and concomitant external radiation therapy followed
by brachytherapy [112,119–123].
In the case of a cisplatin-intolerant patient, NCCN guidelines recommend to use
carboplatin; alternatively, capecitabine/mitomycin, gemcitabine, and paclitaxel can be
considered when cisplatin and carboplatin are unavailable [109]. The NCCN empha-
sizes that the cost and toxicity profiles of radiosensitizing agents should be considered
when selecting an appropriate regimen for treatment, especially when these regimens
are being used for extended-field RT where toxicities may be more severe [109]. The
INTERLACE trial (2012–2022)was a multicenter, randomized phase 3 trial conducted at
32 medical centers, including patients with locally advanced cervical cancer (FIGO stage
IB1 disease with nodal involvement, or stage IB2, IIA, IIB, IIIB, or IVA), to compare stan-
dard cisplatin-based chemoradiotherapy (once-a-week intravenous cisplatin 40 mg/m2
for 5 weeks with 45.0–50.4 Gy external beam radiotherapy delivered in 20–28 fractions
plus brachytherapy to achieve a minimum total 2 Gy equivalent dose of 78–86 Gy) alone
to induction chemotherapy (once-a-week intravenous carboplatin area under the receiver
operator curve 2 and paclitaxel 80 mg/m2 for 6 weeks) followed by standard cisplatin-
based chemoradiotherapy [124]. The findings of this study revealed that short-course
induction chemotherapy followed by chemoradiotherapy significantly improved the sur-
vival of patients with LACC, regardless of the response to induction chemotherapy [124].
In contrast to the benefits of induction before chemoradiotherapy, the OUTBACK study
showed that four cycles of adjuvant paclitaxel 155 mg/m2 plus carboplatin AUC 5 dosed
3 times a week did not improve 5-year OS compared to chemoradiotherapy alone (72%
vs. 71%, HR = 0.90; 95% CI = 0.70–1.17; p = 0.81) [125]. Another phase 3 study (3 ENGOT-
cx11/GOG-3047/KEYNOTE-A18 clinical trial) for LACC (FIGO IB2–IIB node-positive and
stage III–IVA any nodal status) treatment assessed the efficacy and safety of adding to the
standard chemoradiotherapy an anti-programmed death-1 (anti-PD-1) immune checkpoint
inhibitor (ICI)—pembrolizumab. This study compared two groups of patients treated with
five cycles of pembrolizumab (200 mg) or placebo every 3 weeks, plus chemoradiotherapy,
followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks [126]. The
results revealed that the addition of pembrolizumab to the conventional chemoradiother-
apy significantly improved progression-free survival in patients with newly diagnosed,
high-risk, locally advanced cervical cancer [126]. The third interesting recent study for
LACC treatment—the CALLA trial — assessed the efficacy of adding durvalumab, a PD-L1
antibody, with and following chemoradiotherapy [127]. The findings suggest that durval-
umab did not significantly improve progression-free survival in a biomarker unselected,
all-comers population, but the authors suggest its further exploration in patients with
high-tumoral PD-L1 expression [127]. In summary, adding induction chemotherapy (IN-
TERLACE for FIGO stages IB3–IVA, except IIIA and those with nodal disease above the
aortic bifurcation), and, separately, concurrent-maintenance pembrolizumab (KEYNOTE-
Curr. Oncol. 2025, 32, 122 14 of 22

A18 trial in FIGO stages IIIA–IVA), to the standard chemoradiotherapy created two new,
more effective treatment protocols for LACC, from witch INTERLACE has more potential
for worldwide application in LACC than KEYNOTE-A18, because induction chemotherapy
has already demonstrated a 39% relative risk reduction of all-cause mortality compared to
the standard chemoradiotherapy alone [128].

13.3. Recurrent or Metastatic Cervical Cancer (FIGO IVB)

In cases of recurrent or metastatic cervical cancer, the treatment of choice is pallia-
tive chemo- or chemoradiotherapy [109]. According to the NCCN, the preferred first-line
chemotherapy is the combination of platinum-based chemotherapy (cisplatin or carbo-
platin/paclitaxel/bevacizumab), because very often those patients who develop metastasis
have already received concurrent cisplatin/RT and may not respond to single-agent plat-
inum therapy [109].
The NCCN also recommends platinum-containing combination regimens are cis-
platin/paclitaxel (category 1), carboplatin/paclitaxel (category 1), topotecan/paclitaxel/
bevacizumab (category 1), topotecan/paclitaxel, and cisplatin/topotecan as appropriate
alternative options for certain patients [109].
New treatment options are also included in the newest recommendations of many
scientific societies. The KEYNOTE-826 study revealed the efficacy of pembrolizumab
combined with chemotherapy (with or without bevacizumab), with clinically meaningful
improvements in OS, and, therefore, it is now a category 1 preferred treatment for patients
with PD-L1 (CPS ≥1) tumor expression. [109,112,115,128,129].
Another open-label, randomized trial proposes a new first-line therapy option.
BEATcc (ENGOT-cx10/GEICO 68-C/JGOG1084/GOG-3030) compared the anti-PD-L1,
atezolizumab, paclitaxel–platinum plus bevacizumab regimen and proved that the ad-
dition of atezolizumab to a standard bevacizumab plus platinum regimen significantly
improves progression-free and overall survival [130].
In cases of progression after first-line chemotherapy, unfortunately, progression-free
survival was approximately 3 to 6 months [131].
Second-line therapy for recurrent or metastatic cervical cancer options depend on the
tumors’ characteristics and include:
• chemotherapy (paclitaxel, albumin-bound paclitaxel, docetaxel, fluorouracil, gemc-
itabine, pemetrexed, topotecan, vinorelbine, and irinotecan),
• bevacizumab,
• pembrolizumab,
• tisotumab vedotin-tftv,
• cemiplimab,
• Nivolumab for PD-L1–positive tumors,
• Selpercatinib for RET gene fusion–positive tumors,
• TRK inhibitors for NTRK gene fusion–positive tumors (larotrectinib, entrectinib),
• Trastuzumab deruxtecan for HER2-positive tumors,
• biomarkers with their associated targeted treatments as second-line/subsequent thera-
pies [109].

14. Future Directions

Perspectives for new diagnostic and treatment methods:

14.1. Therapeutic Vaccine

In a different strategy than preventive vaccines, which result in neutralizing antibodies,
therapeutic vaccines aim to generate cell-mediated immunity [133]. The main targets are
Curr. Oncol. 2025, 32, 122 15 of 22

oncoproteins E6 and E7, as they play a crucial role in the development of the malignancies
associated with HPV and are expressed in precancerous and cancerous lesions. There are
various types of vaccines tested in clinical trials with promising results, which are based on
• bacterial vector (L. monocytogenes, L. lactis, L. plantarum, L. casei, Salmonella, Shigella,
and E. coli),
• viral vector (adenoviruses, adeno-associated viruses, alphaviruses, and vaccinia virus),
• peptide,
• protein,
• DNA,
• RNA replicon,
• dendritic cell,
• tumor cell [133].
Adoptive T-cell therapy is another strategy that offers more rigorous control over the
magnitude of the targeted response than tumor vaccination, and it showed clinical activity
for LACC in phase-II-trial patients [134,135].
Moreover, Kim et al. conducted a study on electroporation-enhanced immunization
with a rationally designed HPV DNA vaccine (GX-188E) that targeted HPV antigens to
dendritic cells, eliciting a significant E6/E7-specific IFN-γ-producing T-cell response in all
nine cervical intraepithelial neoplasia 3 (CIN3) patients [136].
Another recent study presented the safety and efficacy of a dual-purpose (targeting
active infections as well as established HPV-related malignancies) HPV nanoparticle vaccine
(cPANHPVAX) with eight different HPV L2 peptide epitopes on the E7 oncoantigens from
HPV16 and 18. This new solution can be beneficial for uninfected and infected patients,
acting as both a preventive and curative agent [137].
In conclusion, the combination of HPV therapeutic vaccines with radiotherapy,
chemotherapy, immunomodulators, or immune checkpoint inhibitors creates new im-
provement potential in cervical cancer treatment [135].

14.2. Oncoproteins E6 and E7 Antibodies as Serological Markers

Another method that was assessed in a meta-analysis is HPV16 and HPV18 E6 and
E7 antibodies, and its findings suggest that those markers have high specificity but low
sensitivity to detect cervical cancer or precancerous lesions [138]. A recent meta -analysis
stated in its conclusions that this method is suitable to be used for triaging HPV-positive
women because of its high specificity; nevertheless, oncoprotein-negative women would
not be recommended to undertake routine screening, as they are in need of follow-ups [139].

14.3. Circulating Cell-Free DNA (cfDNA)

A recent study reported on a blood-based test for HPV-specific E7 and L1 genes,
measured in cell-free DNA (cfDNA) extracted from plasma by the use of droplet digital
PCR [140]. This diagnostic method may serve as a tumor marker to guide treatment
and detect early recurrence in cervical cancer, because the statistics showed significant
correlation between high viral load (defined as ≥20 E7 or L1 copies per 20 µL reaction
volume) and increased risk of recurrence and death at 5 years on univariate analysis but
not multivariate analysis [140]. In addition, another study had results that confirmed a
minimally invasive method of detecting HPV E7 cfDNA as a potential tumor marker, with
great specificity and moderate sensitivity for monitoring cervical cancer [141].

15. Conclusions
Since HPV was identified as the necessary cause of cervical cancer, HPV-based tech-
nologies have become central to innovative strategies for both primary and secondary
Curr. Oncol. 2025, 32, 122 16 of 22

prevention. These advancements include the use of HPV testing in screening programs
and the introduction of HPV vaccines for preadolescent girls and young women. When
implemented broadly and strategically, these protocols have the potential to fulfill Pa-
panicolaou’s vision of eradicating cervical cancer by extending the benefits of prevention
to populations in developing regions worldwide. With the continuous advancement of
medical technologies, faster and more convenient methods for conducting such tests are
becoming available. However, the primary strategy for combating cervical cancer remains
testing and vaccination. New clinical trials explore the addition of immunotherapy and
new protocols with induction therapy to the treatment of higher-staged cervical cancers
with promising results for future applications.

Author Contributions: Conceptualization, E.W., E.S., and K.K.; methodology, E.W., M.P.B., and
A.B.-K.; validation, M.P.B., A.B.-K., and A.D.; formal analysis, E.W. and K.K.; writing—original
draft preparation, E.W., K.K., and E.S.; writing—review and editing, E.W., M.P.B., A.D., and A.B.-K.;
visualization, E.S.; supervision, A.B.-K., M.P.B., and A.D. All authors have read and agreed to the
published version of the manuscript.

Funding: This research received no external funding.

Acknowledgments: Figures 1 and 2 in this article were created using Procreate ([Link]
com/, Savage Interactive Pty Ltd., Hobart, TAS, Australia), a digital illustration app for iPad.

Conflicts of Interest: The authors declare no conflicts of interest.

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