Human Papillomavirus: Update in Bridging Basic Science to Clinical and Public Health Innovations

ABSTRACT

Human papillomavirus (HPV), a non‐enveloped, double‐strand DNA viral pathogen, is intricately linked with the onset of various cancers, including cervical cancer and head and neck cancers. The present paper delves into HPV's ancient recognition and significant milestones such as the discovery of its role in oncogenesis and the development of preventive vaccines all the way to routine treatments and newer, cutting‐edge interventions. It highlights therapeutic advancements, including immunotherapies, gene‐editing technologies, and emerging vaccination strategies as well as the personalized HPV‐treatments plans to treat established infections. Challenges, such as vaccine accessibility, therapeutic resistance, and immune evasion, are examined, trying to capture the stigma around HPV and the social complications relating to the disease. The review concludes with future directions emphasizing innovation, equity in treatment access, and the integration of novel therapies to eradicate HPV‐associated diseases and highlight the necessity of Global eradication going forward. This paper aims to traverse the historical origins, molecular pathways, and clinical interventions aimed at understanding and managing HPV.

1. Introduction

Human papillomavirus (HPV) is a non‐enveloped, double‐stranded DNA virus with a distinct evolutionary lineage that, according to limited but hypothetical evidence, may trace back to the time of Neanderthals [1, 2]. Genital warts were first described by Hippocrates (460–377 B.C.), and it is now believed that what he referred to as “round swellings” may have been among the earliest clinical observations of HPV infection [3, 4]. However, it was not until the 20th century that the first papillomavirus was identified in a cottontail rabbit. Nearly 75 years later, in 2008, Professor Harald zur Hausen was awarded the Nobel Prize for establishing the link between HPV infection and cervical cancer, a discovery that transformed the modern understanding of HPV's pathogenic potential [4, 5].

These breakthroughs revealed HPV's role in a broad spectrum of cancers affecting both mucosal and epithelial tissues. While infection with any of the over 150 known HPV types is not, in itself, sufficient to cause cancer [6], epidemiological data indicate a significant association between HPV infection and cancer incidence. Notably, most HPV infections are transient, resolving spontaneously within 6–10 months. It is the high‐risk HPV types particularly types 16 and 18 that are most frequently implicated in malignant progression [1, 5].

The introduction of prophylactic HPV vaccines in the early 21st century, developed by Jian Zhou and Ian Frazer [5], marked a pivotal moment in public health. The bivalent, quadrivalent, and nonavalent vaccines have demonstrated nearly 100% efficacy in preventing diseases caused by targeted HPV types. Despite these successes, the vaccines do not provide therapeutic benefit for individuals already infected or unvaccinated [7].

Over the past two decades, research efforts have increasingly focused on therapeutic interventions for HPV‐related conditions. Current treatments primarily address symptomatic manifestations such as genital and plantar warts. Common modalities include cryotherapy, laser ablation, and photodynamic therapy [8, 9]. Pharmacologic agents, including salicylic acid and 5‐fluorouracil, also play a vital role in treating cutaneous warts [10].

Management of precancerous and cancerous lesions necessitates more advanced interventions. These include surgical excision, conization, and adjunctive use of emerging pharmaceutical agents such as diindolylmethane (DIM) and cidofovir, often in combination with laser therapy or cryotherapy [1, 10].

Despite these advances, eliminating HPV infections at their source remains a formidable challenge. Promising developments in therapeutic strategies including therapeutic vaccines, adoptive T‐cell transfer, and various immunotherapies are currently under investigation [5, 11]. These approaches aim to stimulate and direct the immune system to eradicate persistent infections and prevent malignant transformation. In cases where cancer has already developed, these therapies may empower the immune system to target and destroy cancerous cells with reduced immune evasion [12, 13].

In this narrative review, we provide an overview of HPV, from its historical origins to groundbreaking therapeutic developments, shedding light on the ongoing battle against this ancient yet formidable virus and shedding light on the challenges in the way of global eradication of this virus. Many previous review articles have focused on the epidemiology, molecular biology, and development of vaccine effectiveness for HPV, as well as preventive and therapeutic strategies for HPV‐related cancers [14, 15]. Other reviews have examined the molecular mechanisms underlying HPV infection and oncogenesis, and have summarized advances in screening approaches and public health interventions [16]. This paper emphasizes an interdisciplinary integration of clinical practice and basic science, highlighting how it uniquely bridges fundamental research, clinical application, and public health perspectives. Rather than concentrating on a single aspect, the review synthesizes findings across these domains. It also incorporates updated information on recent therapeutic advancements, including the latest developments in therapeutic vaccines, immunotherapies, and emerging screening technologies that have not been comprehensively addressed in earlier reviews. Additionally, it discusses existing gaps and newly emerging challenges in the field. Overall, this study aims to provide a broader global perspective and to address health equity in the prevention and treatment of HPV as an important and evolving area of inquiry along with synthesize recent advances bridging HPV molecular biology and translational innovations in diagnostics, immunotherapy, and prevention. It is also worth noting that, this article is a narrative review based on a targeted literature search designed to highlight recent translational findings rather than exhaustively cover all HPV‐related publications.

2. Pathogenicity

2.1. Environmental Maintenance, Persistence, and Survival

The environmental stability of human papillomavirus (HPV) has become a growing concern in both clinical and public health settings, challenging the conventional belief that transmission occurs solely through sexual contact. As a non‐enveloped DNA virus with a highly stable capsid, HPV demonstrates exceptional resistance to desiccation, temperature fluctuations, and commonly used chemical disinfectants [17, 18]. Several studies have detected HPV DNA on a variety of inanimate surfaces, including medical instruments such as surgical gloves, speculums, and transvaginal ultrasound probes, raising concerns about potential fomite‐mediated transmission [19, 20, 21, 22]. However, it should be noted that the detection of HPV DNA on various surfaces and objects using PCR‐based diagnostic tests does not necessarily indicate the presence of viable virus or its ability to establish infection [23]. Notably, some researches has shown that while HPV DNA is frequently present in clinical environments, the actual infectivity of these particles may vary depending on factors such as viral load, environmental conditions, and the presence of protective organic matrices [24, 25]. Crucially, under clinically relevant conditions, widely used disinfectants such as glutaraldehyde and ortho‐phthalaldehyde (OPA), previously considered sufficient for high‐level disinfection, have been found to be ineffective against native, infectious HPV virions [24, 26, 27]. In contrast, hypochlorite‐based agents and ultraviolet C (UVC) irradiation have demonstrated significantly greater efficacy in inactivating the virus [27]. Additionally, the detection of HPV DNA in surgical smoke has raised the possibility of airborne transmission, particularly during electrosurgical procedures in dermatology and gynecology, although this route remains unverified [28, 29]. These findings underscore the critical distinction between the detection of viral DNA and the presence of viable, infectious virions an area still insufficiently addressed in the current literature [25]. The virus's ability to persist in exfoliated epithelial cells and remain viable for extended periods under dry conditions further complicates infection control strategies [17, 30, 31]. Taken together, these observations highlight the urgent need for enhanced environmental surveillance, rigorous virucidal testing using native HPV virions, and a comprehensive reassessment of disinfection protocols in both clinical and community settings. Addressing these environmental reservoirs is essential for reducing the risk of non‐sexual transmission and for ensuring safer healthcare practices. Table 1 summarizes several studies that have investigated the stability of HPV on various surfaces, including moist biological soils, as well as its transmission via fomites such as contaminated ultrasound probes, towels, and other objects.

Table 1.

HPV persistence and disinfectants efficacy.

Ref	Method/Test format	Surface/Matrix tested	Viral material/Surrogate	Main outcome (Practical takeaway)
[24]	Suspension assays (virions + disinfectant, neutralize, infectivity readout); contact time ~45 min	Aqueous suspensions (laboratory assays), authentic virions produced in organotypic (raft) culture	Authentic HPV‐16 native virions and HPV16 quasivirions	HPV‐16 is unusually resistant: resistant to GTA and OPA; susceptible to hypochlorite and to higher‐concentration peracetic acid/silver formulations (quasivirus slightly more susceptible to some agents). Implication: some clinical “sterilants” fail in suspension tests for native HPV.
[26]	Hard‐surface carrier test: virus dried onto carriers with 5% protein soil, then processed with device/chemicals; infectivity qRT‐PCR readout	Hard carriers' representative of ultrasound probe plastics (dried with protein soil)	Native HPV‐16 and HPV‐18 virions	Automated sonicated hydrogen peroxide device → reduction (virucidal). Cidex® OPA→ minimal effect. Hypochlorite included as positive control. Practical: use H2O2‐based HLD (or validated HLD) for endocavitary probes rather than relying on OPA alone.
[27]	Hard‐surface carrier test: virus dried with soil or hard water, automated UVC device tested; qRT‐PCR infectivity assay	Plastic carriers mimicking ultrasound probe surfaces, with 5% BSA or 4 ppm hard water	Native HPV‐16 and HPV‐18 virions	High‐level UVC achieved inactivation under soil/hard water conditions; HPV is highly resistant to OPA. Practical: UVC or validated H2O2 systems are effective options for probe reprocessing.
[32]	Environmental persistence experiments: pseudovirus/native virus mixed into PBS, CVS or serum; measured infectivity over time ± desiccation	Wet droplets in PBS/CVS/serum; also desiccated on surfaces (simulated)	HPV‐16 pseudoviruses & native HPV‐16 from clinical CVS	HPV remains infectious for days in wet conditions ( ≥ 7 days detectable infectivity in PBS; lower but persistent infectivity with CVS or desiccation). Intact native HPV detected after 5 days. Practical: fomites and contaminated instruments/towels can plausibly harbor infectious HPV for multiple days.
[33]	Quantitative suspension tests comparing multiple chemical biocides against HPV16 pseudovirus and SV40	Suspension format (laboratory tests)	HPV‐16 pseudovirus and SV40 (simian virus 40) as surrogate	SV40 was a reasonable surrogate for some disinfectants (isopropanol, GTA, QAC, OPA) but not universally, some agents behaved differently vs HPV pseudovirus (e.g., ethanol and some PAA results). Practical: surrogate choice matters; results from SV40 or pseudovirus must be interpreted cautiously and, where possible, confirmed with native virions or standardized carrier tests.

Abbreviations: CVS, cervicovaginal secretions; DPTA, dodecyldipropylentriamin; GTA, glutaraldehyde; OPA, ortho‐phthalaldehyde; PAA, peracetic acid; QAC, quaternary ammonium compounds with alkylamines; UVC, ultra‐violet C.

2.2. Infection

HPV primarily targets the basal layer of stratified squamous epithelia, such as the cervical epithelium, gaining access through micro‐abrasions or regions where basal cells are exposed or more accessible [34, 35, 36]. Upon entry, the virus is internalized via endocytosis and transported to the trans‐Golgi network and Golgi apparatus. The minor capsid protein L2 plays a critical role in mediating this intracellular trafficking [37, 38]. During mitosis, when the nuclear envelope disassembles, the viral genome gains access to the nucleus. Once inside, the viral DNA localizes to promyelocytic leukemia nuclear bodies (PML‐NBs), which serve as hubs for viral transcription and replication [9].

2.3. Replication

HPV exploits the natural differentiation process of epithelial cells to complete its replication cycle. After entry through micro‐abrasions, the virus uses heparan sulfate proteoglycans and integrins to facilitate binding and internalization into basal keratinocytes [9, 39, 40]. Once inside the host cell, the viral genome is transported to the nucleus, where initial genome amplification occurs. During this early phase, the expression of early genes such as E1 and E2 initiates, regulating viral DNA replication and transcription (2, 9, 20). The E2 protein not only maintains the viral genome as an episome remaining separate from the host DNA, but also acts as a transcriptional repressor of the viral oncogenes E6 and E7 [36, 41].

In the maintenance phase, the virus persists within the basal layer of the epithelium, replicating at low levels and producing a limited number of virions. During this stage, E6 and E7 are expressed at low levels to promote host cell proliferation, thereby supporting viral genome replication [9, 42].

As infected cells undergo differentiation and migrate toward the surface of the epithelium, HPV enters the differentiation‐dependent amplification phase. Here, viral replication intensifies. Expression of E6 and E7 increases, while E2 expression is downregulated, leading to loss of cell cycle control and unregulated cellular proliferation. The E4 protein contributes by disrupting the cytokeratin network in the upper epithelial layers, facilitating virion release and enhancing viral genome amplification [11, 43].

In the late phase, L1 and L2, the major and minor capsid proteins, are expressed in the uppermost differentiated epithelial cells. These proteins assemble into mature virions, which are subsequently released as the infected epithelial cells are shed [42].

A key step in the development of HPV‐associated malignancies is the integration of the viral genome into the host's chromosomal DNA [39, 44]. This often results in the deletion or disruption of the E2 gene, removing its inhibitory control over E6 and E7. The resulting overexpression of E6 and E7 drives uncontrolled cell proliferation and contributes to malignant transformation [40].

2.4. Immune Evasion and Oncogene Tendencies

Although the majority of HPV infections are cleared spontaneously by the host immune system within a few years, a subset of infections persists, significantly increasing the risk of developing cervical and other intraepithelial lesions [12]. The persistence of HPV is largely mediated by its oncoproteins E6, E7, and E5 which enable the virus to evade immune detection and subvert host antiviral mechanisms [8, 45]. The E6 oncoprotein contributes to immune evasion and tumorigenesis by targeting and degrading the tumor suppressor protein p53, a key regulator of cell cycle arrest and apoptosis. The inactivation of p53 allows cells harboring DNA damage to evade apoptosis, leading to genomic instability and increasing the risk of malignant transformation. Simultaneously, E7 binds to and functionally inactivates the retinoblastoma protein (pRb), another critical cell cycle regulator, thereby promoting unchecked cellular proliferation and the formation of precancerous lesions [13, 46].

In addition to E6 and E7, the E5 protein impairs antigen presentation by interfering with the expression and trafficking of major histocompatibility complex (MHC) class I and II molecules, limiting the ability of cytotoxic T cells to recognize and eliminate infected cells [47, 48]. E6 and E7 further dampen the antiviral response by inhibiting the production and signaling of type I interferons. This is accomplished through their interactions with key immune signaling molecules, including Interferon Regulatory Factor 3 (IRF3) and the Stimulator of Interferon Genes (STING) pathway [46]. HPV also suppresses components of the innate immune system. It downregulates the expression of pattern recognition receptors (PRRs), such as Toll‐like receptors (TLRs), which are essential for initiating antiviral signaling cascades. Moreover, persistent HPV infection is associated with the induction of immunosuppressive cytokines, including interleukin‐10 (IL‐10) and transforming growth factor‐beta (TGF‐β), creating a local microenvironment that inhibits immune activation and promotes viral persistence [39]. HPV can also reduce the expression of chemokines that recruit immune cells to the site of infection, thereby impairing immune surveillance.

A critical event in HPV‐mediated oncogenesis is the integration of the viral genome into the host DNA. This integration frequently disrupts the E2 gene, which normally represses E6 and E7 expression. Loss of E2 leads to the sustained overexpression of E6 and E7, further accelerating cellular transformation and progression to cancer [49, 50] (Figure 1).

Figure 1.

HPV16 genome structure and functions. The picture shows HPV genes in two main categories and three sub‐categories. Early and Late genes are respectively abbreviated as E and L genes. E1, E2, E4 and E5 genes are host cellular replication genes and cell signaling genes. E6 and E7 are oncogenes genes of the virus. L1 and L2 are Capsid Protein genes.

2.5. Environmental Sterilization

Although HPV exhibits exceptional resistance to many commonly used disinfectants, effective sterilization within clinical environments is critical to mitigating the risk of fomite‐mediated transmission. In some studyes demonstrated that while native HPV16 virions and quasivirions are susceptible to sodium hypochlorite and high concentrations of peracetic acid–silver formulations, they remain viable following exposure to high‐level disinfectants such as glutaraldehyde and ortho‐phthalaldehyde [24, 51]. Subsequent investigations in clinically relevant conditions confirmed these findings, showing that the infectivity of HPV16 and HPV18 on ultrasound probes and nasendoscopes was reduced using chlorine dioxide‐based systems and sodium hypochlorite, even in the presence of organic soil loads. Furthermore, a hard‐surface carrier test revealed that an automated hydrogen peroxide (H₂O₂) sonication system achieved reductions in HPV16/18 infectivity, whereas OPA was significantly less effective, reduction [26, 51]. Ultraviolet‐C (UVC) irradiation has also demonstrated rapid virucidal efficacy, inactivating high‐risk HPV types on probe surfaces within minutes and offering a non‐chemical alternative for disinfection [27, 52]. Collectively, these findings highlight a critical disparity in sterilant effectiveness: oxidizing agents (e.g., hydrogen peroxide, chlorine dioxide, sodium hypochlorite) and physical methods (UVC) consistently outperform aldehyde‐based disinfectants in inactivating HPV. To ensure patient and healthcare worker safety, sterilization protocols must be validated using native virions under realistic clinical conditions, including organic contamination. Incorporating these advanced disinfection technologies into routine infection control practices is essential for reducing the risk of non‐sexual HPV transmission.

2.6. Diagnostic/Prognostic Test

The most recent diagnostic approach for detecting human papillomavirus (HPV) infection is the HPV mRNA test, commercially known as the APTIMA® assay, which was approved by the U.S. Food and Drug Administration (FDA) in 2011. This test detects whether specific HPV genotypes are actively driving oncogenic processes. It targets two viral oncogenes, E6 and E7, whose expression indicates viral integration into the host genome at lesion sites and the potential for malignant transformation [53]. Low expression levels of these genes may suggest minimal viral activity, implying a reduced risk of progression to cancer, regardless of the virus's physical presence in the host.

Biomarkers are biological molecules naturally present in the human body or in pathogens such as viruses. They serve as indicators for disease detection, prognosis, and monitoring therapeutic response. Biomarkers play a crucial role in cancer screening and early diagnosis, forming an essential part of personalized and precision medicine. The identification of these biomarkers enhances early detection, treatment monitoring, and informed clinical decision‐making [54].

HPV‐related biomarkers, particularly those used in genetic‐based diagnostic tests, are broadly categorized into two groups based on their origin:

Human‐derived biomarkers: These biomarkers are molecules endogenously produced in the human body, whose expression or activity changes during carcinogenic processes. Prominent examples include:

• Cell cycle proteins:

  p16INK4a: A key biomarker in HPV‐associated lesions, p16INK4a is abnormally overexpressed in cells where the cell cycle is dysregulated. Elevated expression of this protein is frequently observed in precancerous cervical lesions [55].

  Ki‐67: A nuclear protein expressed exclusively in proliferating cells, serving as a marker of cellular proliferation [56].

• Serum proteins (detectable in blood):

  Tumor‐associated markers such as SCC‐Ag (Squamous Cell Carcinoma Antigen), CA‐125, and CYFRA are elevated in some head and neck cancers as well as cervical cancers, aiding in treatment response monitoring [57, 58].

• Non‐coding RNAs:

  microRNAs (miRNAs) (e.g., miR‐21, miR‐34a) and long non‐coding RNAs (lncRNAs) (e.g., HOTAIR) that regulate gene expression relevant to carcinogenesis [59].

• Human DNA methylation patterns:

  In cancer, tumor suppressor genes are frequently silenced by epigenetic modifications such as DNA methylation. Methylation of genes such as CADM1, MAL, and FAM19A4 serves as a biomarker for precancerous lesions [60].

• Circulating free DNA (cfDNA) and circulating tumor DNA (ctDNA):

  These are small fragments of DNA present in the bloodstream. In cancer patients, dying tumor cells release DNA into circulation, which can be detected and quantified. cfDNA/ctDNA holds significant promise in non‐invasive diagnostics, prognosis, and monitoring of treatment responses [61].

• Immunohistochemistry (IHC) markers:

  Using antibody‐based staining on biopsy samples, proteins such as p16, Ki‐67, p53, Bcl‐2, COX‐2, and CD44 can be visualized. IHC is a rapid, cost‐effective, and widely accessible method providing critical insights into the pathological status of cells [62].

  Virus‐derived biomarkers: These biomarkers originate directly from the HPV genome or its gene products, indicating the presence or activity of the virus:

• Viral oncogenes E6 and E7:

  These are the principal oncogenes of HPV. E6 and E7 inactivate the key cell cycle regulators p53 and Rb, respectively, leading to uncontrolled cellular proliferation [63].

• HPV DNA:

  The presence and genotype of HPV DNA can be detected using molecular techniques such as polymerase chain reaction (PCR) or Hybrid Capture 2. Among the many HPV types, HPV16 and HPV18 are recognized as the most oncogenic [64].

• Viral RNA (mRNA):

  Detection of viral transcripts, particularly E6/E7 mRNAs, indicates active viral replication. mRNA‐based assays offer greater specificity than DNA tests for identifying clinically significant infections [65].

• Viral DNA methylation:

  Epigenetic alterations within the HPV genome are associated with disease progression. Analyzing viral DNA methylation patterns provides valuable information on lesion severity and cancer risk [66].

• Combined Diagnostic Tests:

Dual‐staining assays for p16/Ki‐67 are well‐established diagnostic tools. A positive dual‐staining result—where both markers are co‐expressed in a single cell—indicates disruption of the cell cycle due to active high‐risk HPV infection.

Despite significant laboratory advancements, a gap remains between these innovations and routine clinical implementation. In general, how new technologies compete with established PCR‐based methods in terms of cost, sensitivity, and feasibility is still under discussion. Emerging HPV detection approaches, such as isothermal amplification and CRISPR‐based diagnostics, offer notable advantages over conventional PCR in cost, speed, and field‐deployability, while demonstrating comparable sensitivity in many studies [67]. However, due to limited large‐scale validation using diverse and real‐world clinical samples—particularly self‐collected or non‐invasive specimens along with the lack of standardized protocols and reproducibility of laboratory data, issues related to cost, supply chains, and platform availability (especially for CRISPR and biosensor‐based devices) must be addressed. These considerations are particularly critical in resource‐limited settings before such technologies can fully replace or complement PCR‐based methods.

3. Traditional Treatment

3.1. Management of Warts

Currently, there is no specific cure for HPV infection itself. Treatment strategies focus on managing the clinical manifestations particularly warts and precancerous lesions rather than eradicating the virus. Most HPV infections are transient and resolve spontaneously within one to 2 years, owing primarily to the host immune response. The immune system plays a critical role in viral clearance, and for this reason, routine screening or active case‐finding in asymptomatic individuals is generally not recommended [10]. It is important to note that the treatment of HPV‐related lesions does not necessarily eliminate the underlying viral infection. Advances in the management of HPV‐associated diseases, particularly precancerous cervical lesions, include procedures such as loop electrosurgical excision of the transformation zone (LEEP) and ablative therapies like cryotherapy and laser ablation. While effective, these procedures carry potential risks, including miscarriage and premature birth when performed during pregnancy in individuals with genital warts. Despite the efficacy of ablative and surgical techniques such as cryotherapy, laser therapy, and electrocautery, recurrence rates remain high. Topical agents such as imiquimod, podophyllin, and trichloroacetic acid (TCA) are frequently used in the treatment of genital and cutaneous warts [44]. Imiquimod functions as an immune response modulator, whereas podophyllin and TCA act as cytotoxic agents. Interferons, cytokines with antiviral, antiproliferative, and immunomodulatory effects have also been investigated for their therapeutic potential. These can be administered topically, intralesionally, or systemically. A systematic review published in 2009 reported that topical interferon showed efficacy in the treatment of genital warts; however, systemic administration did not demonstrate statistically significant clinical benefit. Photodynamic therapy (PDT) has emerged as an alternative therapeutic modality for HPV‐associated lesions [2]. PDT involves the application of a photosensitizing agent followed by exposure to a specific wavelength of light, resulting in selective destruction of infected or dysplastic cells. PDT is increasingly employed for the treatment of precancerous cervical lesions and early‐stage cervical carcinoma. Additionally, some studies suggest that PDT may contribute to the regression of HPV infections, particularly in post‐conization or postmenopausal patients [8, 9].

3.2. Treatment of HPV‐Related Cancers

3.2.1. Surgery

Surgical resection is often the primary treatment modality for early‐stage, localized HPV‐associated cancers. The extent of surgical intervention depends on several factors, including tumor size, anatomical location, and disease stage [9, 68].

3.2.2. Radiotherapy

Radiation therapy employs high‐energy ionizing radiation to destroy malignant cells. It may be used as a standalone treatment or in combination with chemotherapy, particularly in cases of locally advanced disease [9, 68].

3.2.3. Chemotherapy With Cisplatin

Cisplatin is a platinum‐based chemotherapeutic agent widely used in the treatment of HPV‐associated malignancies, especially cervical cancer. It functions by interfering with DNA repair mechanisms, inducing DNA damage, and triggering apoptosis in cancer cells [69]. However, its clinical utility is often compromised by the development of chemoresistance and significant side effects. To enhance efficacy and reduce toxicity, combination therapies involving cisplatin and other agents have gained attention [41, 49, 69]. One of the major limitations of cisplatin is its lack of target specificity, leading to systemic toxicity and collateral damage to healthy cells [69, 70]. Consequently, co‐administration with natural compounds or novel therapeutics has been explored to overcome resistance and minimize adverse effects. For instance, studies have demonstrated that combining cisplatin with medicinal plant extracts can potentiate its cytotoxic effects while reducing required dosages. A notable example is the combination of cisplatin with an extract of Vitex pseudo‐negundo, which resulted in enhanced cervical cancer cell apoptosis, increased reactive oxygen species (ROS) production, cell cycle arrest, and reduced cell migration compared to cisplatin alone [69]. Gene therapy approaches, such as the co‐delivery of cisplatin with small interfering RNA (siRNA), offer another promising strategy. Targeting the HPV E6 oncogene using E6‐specific siRNA has been shown to sensitize cervical cancer cells to cisplatin, reduce their proliferation and metastatic potential, and enhance apoptosis. This approach also allows for the use of lower cisplatin doses, potentially reducing systemic toxicity [70].

An essential factor in selecting the most effective treatment for papillomavirus infection is the presence of interdisciplinary collaboration and scientific dialog between virologists and immunologists, who possess a comprehensive understanding of viral pathogenesis and clinicians such as oncologists or gynecologists. This collaborative approach ensures a more accurate interpretation of disease mechanisms and facilitates the development of targeted, patient‐specific therapeutic strategies.

3.2.4. Other Non‐Surgical Treatments

Cryotherapy: A localized treatment that uses extreme cold to freeze and destroy abnormal cervical tissue [71].

Thermocoagulation: A heat‐based method for ablating dysplastic cervical tissue, often employed in resource‐limited settings [9].

Focused ultrasound (FUS): High‐intensity focused ultrasound beams are used to non‐invasively ablate tumor tissue with precision [9].

3.2.5. Botanical Drugs

While most research focuses on conventional biomedical approaches for treating HPV‐related complications, increasing attention is being paid to complementary strategies, particularly those derived from Traditional Chinese Medicine (TCM). Certain plant‐derived compounds have demonstrated immunomodulatory and chemosensitizing properties that may enhance the efficacy of existing treatments. For example, the Zera peptide, a self‐assembly domain derived from the maize gamma‐zein seed storage protein has shown promise as an adjuvant by enhancing immune responses against HPV antigens. Adjuvants function by stimulating innate immune receptors and promoting efficient antigen presentation, thereby amplifying the adaptive immune response [10, 69].

In addition to their immunostimulatory effects, botanical agents may also sensitize cancer cells to chemotherapeutic agents, such as cisplatin. This chemosensitization allows for the use of lower drug doses, potentially minimizing adverse effects. Research indicates that certain plant extracts, including flavonoids, can enhance the responsiveness of cisplatin‐resistant cancer cells, exerting a synergistic cytotoxic effect that augments overall treatment efficacy [69]. Furthermore, many botanical compounds possess antioxidant properties that may protect healthy cells from oxidative damage during chemotherapy. These agents may also contribute to reversing or reducing the drug resistance developed by cancer cells, thereby improving therapeutic outcomes [69].

3.2.6. Limitations of Current Treatments

While surgery is effective for treating localized HPV‐related cancers, it may not be suitable for all patients particularly those with advanced or metastatic disease [9, 72]. Surgical procedures can also carry the risk of complications and long‐term side effects, which vary depending on the extent and location of the intervention.

Radiation therapy, although effective in targeting tumor cells, can damage surrounding healthy tissues, leading to adverse effects such as fatigue, skin irritation, and organ dysfunction [2]. Furthermore, concerns remain about the long‐term consequences of radiation exposure.

Chemotherapeutic agents like cisplatin are commonly used in HPV‐related cancers, including cervical cancer. While cisplatin disrupts DNA repair mechanisms and induces apoptosis in cancer cells, its use is associated with systemic toxicity, affecting various organs and causing side effects such as nausea, vomiting, alopecia, and immunosuppression [10, 73]. One of the most significant challenges in chemotherapy is the development of resistance to cisplatin, which can severely limit its clinical efficacy [34, 45].

Cisplatin resistance can be either intrinsic (pre‐existing before treatment) or acquired (developing during therapy) [69]. Several cellular mechanisms contribute to resistance, including reduced drug uptake, enhanced detoxification, increased drug efflux, improved DNA repair capacity, and evasion of apoptosis. High‐risk HPV oncoproteins E6 and E7 have also been implicated in promoting resistance by disrupting normal cell cycle control and apoptotic signaling pathways [7, 40].

In addition, the tumor microenvironment plays a critical role in modulating therapeutic responses. Factors such as hypoxia (low oxygen levels) can impair drug delivery and alter cellular behavior, further contributing to chemoresistance [13, 74].

Addressing cisplatin resistance is a major focus of current research. Strategies include combination therapies with other chemotherapeutic or natural agents, gene therapy approaches targeting resistance‐related pathways (e.g., those involved in drug efflux or DNA repair), and the development of novel cisplatin analogs with improved efficacy and reduced resistance potential [46]. These approaches aim to restore drug sensitivity and enhance the overall effectiveness of treatment in HPV‐associated malignancies (Table 2).

Table 2.

Different treatment options for HPV.

Categories	Type of treatment	Descriptions and obstacles	Ref.
Herbal medicine	TCM	There are several prominent herbal treatments in this category, namely Paiteling, Chai Hu, Youdujing, Pinella Extract, and Zibai Gel. Though, it must be mentioned that the results are inconsistent in treating HPV‐related complications.	[1]
	Other	Reports mention that other natural remedies such as Myrtle, Curcumin, Realgar, Securidaca‐Saponins, Fiscus carica Latex, Juglone, and Pine Tree Fruit Smoke. Like TCM, these other methods show inconsistencies in helping with the treatment of HPV‐related complications.	[9]
Treatment of HPV‐related cancers	Surgery	Surgical resection is often the primary treatment for localized HPV‐related cancers in early stages. The extent of surgery depends on tumor size, location, and stage.	[9, 49, 68]
	Radiotherapy	Radiation therapy utilizes high‐energy rays to kill cancer cells. It can be used alone or in combination with chemotherapy, especially for locally advanced cancers.	[9, 48, 75]
	Chemotherapy	Chemotherapy drugs, such as cisplatin, are commonly used to kill rapidly dividing cancer cells. However, chemoresistance can develop, leading to treatment failure.	[10, 73]
	Other	Photodynamic Therapy (PDT), Cryotherapy, Thermocoagulation, and Thermocoagulation.	[1, 10]
Management of warts	—	Loop excision of the transformation zone or ablative techniques such as cryotherapy or laser therapy. Various topical agents, such as imiquimod, podophyllin, and trichloroacetic acid. Topical interferon. Photodynamic Therapy (PDT).	[2]

4. Adjunctive and Experimental Therapies

4.1. Traditional Chinese Medicine (TCM)

Paiteling: This TCM formulation, containing ingredients like folium, sophora, cnidium, gall, and javanica oil, is known to inhibit HPV by disrupting mitochondrial and other cellular membranes, leading to necrosis. It has been studied for treating cervical HPV infection [1, 9].

Chai Hu: Derived from the roots of Bupleurum Chinese, Chai Hu is known to interfere with HPV DNA expression in genital warts [1, 76]. Evidence remains limited and mechanistic in nature.

Youdujing: This TCM preparation has been reported to reverse cervical lesions in patients at high risk of HPV infection [1, 38, 76]. These findings are preliminary.

Pinellia Extract: Treatment with a fraction of Pinellia extract has been shown to reduce the expression of HPV E6 and E7 mRNA and protein levels [1]. Clinical relevance remains uncertain pending further research.

Zibai Gel: This TCM gel has been clinically studied for treating high‐risk HPV infection of the cervix [1]. Though methodological constraints warrant cautious interpretation.

4.2. Other Herbal and Natural Remedies

A growing body of research has explored the use of herbal and plant‐based compounds particularly from TCM, as adjuncts or alternatives in the treatment of HPV‐related diseases. These natural agents offer diverse mechanisms of action, including immune modulation, antiviral activity, and chemosensitization. However, most findings arise from preclinical studies, small trials, or heterogeneous methodologies, and therefore should be viewed as preliminary.

Myrtle: Vaginal suppositories containing myrtle have been evaluated in a randomized clinical trial for the treatment of cervicovaginal HPV infections, demonstrating potential therapeutic benefits [9].

Curcumin: The topical application of polyherbal creams containing Curcuma longa (turmeric) or its active compound curcumin has shown promise in clearing cervical HPV infections in a phase II clinical trial [9].

Realgar: A traditional mineral‐based remedy in TCM, realgar (As₄S₄) has been found to induce apoptosis in HPV16‐positive cervical cancer cells. This effect appears to be mediated via the HPV16 E7 oncoprotein, suggesting that realgar may disrupt pathways involved in E7‐driven cellular transformation and survival [9, 49].

Securidaca‐Saponins: These naturally occurring compounds have been identified as inhibitors of the survival proteins AKT, MCL‐1, and BCL2L1 in cervical cancer cells. By modulating key apoptosis‐related pathways, securidaca‐saponins may promote cancer cell death [9].

Ficus carica Latex: Extracts from the latex of Ficus carica (fig tree) have demonstrated biological activity that may be beneficial in the treatment of HPV‐associated cervical cancers, although further mechanistic studies are warranted [9].

Juglone: A naphthoquinone compound found in plants such as black walnut (Juglans nigra), juglone selectively inhibits the proliferation of HPV‐positive cervical cancer cells. While the precise molecular targets remain to be elucidated, its specificity suggests interference with viral replication or host pathways dysregulated by HPV [9].

Pine Tree Fruit Smoke: Although not a conventional herbal treatment, anecdotal evidence from a case report indicates potential efficacy of pine tree fruit smoke in the treatment of warts, suggesting a need for further investigation [9].

Vitex pseudo‐Negundo: This plant has shown promising anticancer activity when combined with cisplatin in the treatment of cervical cancer. It exhibits antioxidant, growth‐inhibitory, and apoptosis‐inducing properties. Studies indicate that this combination enhances cisplatin's efficacy, reduces toxicity, and inhibits tumor progression [69].

4.3. Other Supplementary, Vitamin, and Medications

Recent clinical studies have identified a number of adjunctive therapies that may enhance the clearance of HPV, particularly in cases of persistent or chronic HPV infection. Nevertheless, findings should be interpreted cautiously given the variability in study design and sample size. A clinical trial evaluating Active Hexose Correlated Compound (AHCC), a cultured extract derived from shiitake mushrooms, demonstrated that daily administration of 3 g AHCC for 6 months in women with high‐risk HPV infections persisting for over 2 years resulted in over 58% clearance rate, compared to in the placebo group. Sustained viral suppression was associated with enhanced T‐cell and interferon‐gamma (IFN‐γ) responses, alongside decreased interferon‐beta (IFN‐β) expression [77]. In a separate randomized, placebo‐controlled trial, oral zinc sulfate administered for 3 months significantly reduced HPV persistence and inhibited the progression of cervical lesions [78]. Additional evidence from smaller randomized studies has supported the efficacy of a multi‐agent oral combination comprising epigallocatechin gallate (EGCG), folic acid, vitamin B12, and hyaluronic acid, which led to an HPV clearance [79]. Topical antioxidant treatments such as DeflaGyn® gel, containing silicate dioxide, citric acid, and selenite, have also demonstrated significant cytological improvement, far exceeding spontaneous remission rates [80]. Furthermore, recent data suggest that nanocurcumin supplementation may result in clearance rate, in individuals with HPV related cervical cancer [81]. Preliminary investigations into medicinal mushrooms, including Ganoderma lucidum and Trametes versicolor (turkey‐tail), indicate potential immunomodulatory benefits, although current evidence remains limited [82]. Collectively, these nutraceuticals exhibit synergistic antiviral and immune‐enhancing properties, with generally favorable safety profiles. Nonetheless, the available data are constrained by small sample sizes and methodological heterogeneity, underscoring the urgent need for well‐designed, large‐scale randomized controlled trials to determine optimal dosing regimens, underlying mechanisms, and long‐term clinical efficacy.

In summary, there is currently no definitive cure for human papillomavirus (HPV) infection. The eventual clearance of the virus or the progression to HPV‐related disease largely depends on the efficacy of the host immune response (Figure 2). Table 3 highlights some of the key immune cells involved in the viral clearance process, emphasizing their critical roles in modulating the outcome of HPV infection.

Figure 2.

The interplay between the host immune response and viral infection plays a pivotal role in viral clearance. In fact, the host's immune system is the most critical factor in the control and elimination of viral pathogens. All therapeutic interventions, whether pharmacological treatments or strategies aimed at improving the patient's psychological and physical well‐being are ultimately designed to enhance and support the immune system, empowering it to effectively eradicate the virus from the body.

Table 3.

Immune components involved in papillomavirus clearance.

Ref.	Function in HPV clearanace	Immune component
[83, 84, 85]	Detect HPV via TLRs, cGAS/IFI16; produce IFN, cytokines	Keratinocytes & PRRs
[85, 86]	Kill infected cells, secrete IFN‐γ/TNF‐α, activate adaptive immunity	NK/NKT Cells
[87, 88]	Process antigens; prime CD4⁺ and CD8⁺ T cells	APCs (DCs/Langerhans)
[86, 89, 90]	Support CTLs, macrophages; secrete IL‐2, IFN‐γ	CD4 Th1 Cells
[91, 92]	Destroy infected keratinocytes via perforin/granzyme	CD8 CTLs
[93, 94]	Maintain local immunity and rapid recall responses	Tissue‐resident T cells
[95]	Neutralize extracellular virions, less effective in natural infection without vaccination	B cells/Antibodies

5. New Horizons of Treatment

Treatment of human papillomavirus (HPV)–associated cancers is increasingly shifting toward targeted and immunogenic strategies that specifically address the viral oncoproteins E6 and E7. Immunotherapy represents the leading approach in this field, followed by therapeutic vaccines designed to elicit robust cytotoxic T lymphocyte (CTL) responses against infected cells. Gene therapy has also emerged as a novel strategy aimed at directly disrupting the E6/E7 oncogenes through technologies such as CRISPR/Cas9 and TALEN [96]. Table 4 provides a summary of these emerging strategies, highlighting promising therapeutic avenues that may significantly improve outcomes for patients with HPV‐related malignancies.

Table 4.

Different Types of Therapeutic approaches for HPV.

Therapeutic class	Therapeutic agent	Modality/Strategy	Mechanism of action	Development stage	Representative trial(s)	Key outcomes	Ref.
Immunotherapy	Immune Checkpoint Inhibitors (ICIs)	Monoclonal antibodies (e.g., anti‐PD‐1: pembrolizumab, nivolumab)	Block PD‐1/PD‐L1 pathway → enhance T‐cell‐mediated anti‐tumor immunity	Clinical — Phase I/II/III	KEYNOTE‐158 (pembrolizumab in recurrent/metastatic HPV+ cancers)	Encouraging responses in recurrent/metastatic disease, particularly with high PD‐L1 expression; durable responses in a subset of patients. FDA‐approved indications for some HPV+ malignancies.	[40, 49, 74, 97, 98]
	Adoptive T‐Cell Therapy (ACT)	TILs or genetically engineered T cells (e.g., CAR‐T targeting E6/E7)	Ex vivo expansion and reinfusion of HPV‐specific T cells → direct cytotoxicity against HPV+ tumor cells	Early‐phase clinical (Phase I/II)	Small trials of CAR‐T or TIL therapy in cervical and head & neck cancers	Early‐phase studies show feasibility, T‐cell persistence, and preliminary anti‐tumor activity; clinical efficacy still under evaluation. Experimental, not standard‐of‐care.	[13, 47, 73, 99]
Therapeutic vaccines	Peptide‐Based	Synthetic E6/E7 peptides	Stimulate cytotoxic T lymphocyte (CTL) responses	Phase I/II	SLP vaccine in HSIL, DPX‐E7, ISA 101	Limited clinical efficacy; some immunologic response detected but minimal lesion regression.	[1, 2, 40, 100, 101]
	Viral Vectors	Modified vaccinia virus (MVA), adenovirus	Deliver HPV antigens to elicit CTL response	Phase I/II	TG4001 (MVA‐E6/E7 + IL‐2), TA‐HPV	TG4001: 48% response rate in CIN2/3 phase II trial; TA‐HPV induced immune responses, clinical outcomes confounded by surgery.
	Bacterial Vectors	Attenuated Listeria monocytogenes	Delivers HPV antigen to APCs, stimulates CTLs	Phase I/II	ADXS11‐001 in anal cancer and HNC	88.9% progression‐free survival in anal cancer phase II; serious adverse events reported, including one death.
	DNA‐Based	Plasmids encoding E6/E7 ± adjuvants (e.g., IL‐12)	Induce antigen‐specific T‐cell immunity	Phase I–III	VGX‐3100 (CIN2/3), pNGVL4a‐CRT/E7, MEDI‐0457	VGX‐3100: Safe and efficacious in Phase IIb; ongoing Phase III. pNGVL4a‐CRT/E7: 30% lesion resolution, trial terminated early in HNC due to adverse events.
	RNA‐Based	mRNA encoding HPV antigens (LNP formulations)	Induce antigen expression → CTL activation	Preclinical/early clinical	gDE7 mRNA vaccines (mouse models), HPV mRNA‐LNP	Robust T‐cell responses and tumor regression in mice; human efficacy not yet established.
	Plant‐Derived	HPV antigen expressed in plants	Oral or parenteral immunization to induce CTLs	Preclinical	Experimental plant‐expressed HPV vaccines	Advantages: scalable, low cost, adjuvant properties; clinical data limited, early‐stage.
Gene therapy	CRISPR/Cas9	Gene editing to disrupt E6/E7 oncogenes	Restore tumor suppressor function (p53/Rb), inhibit tumor growth	Preclinical; early clinical Phase I trials ongoing	NCT03057912 (TALEN), NCT02800369 (CRISPR/Cas9)	Preclinical: tumor suppression and p53 restoration; clinical trials ongoing — experimental, not yet standard‐of‐care.	[69, 73, 102]
	siRNA	Sequence‐specific RNA silencing of E6/E7	Reduce oncogene expression → increase apoptosis, enhance chemotherapy sensitivity	Preclinical	Co‐treatment with E6‐siRNA + oxaliplatin in vitro	Synergistic effect with chemo in cervical cancer cells; stability and delivery remain challenges.	[70, 103]
Nanobodies	Nanobody Therapeutics	Single‐domain antibodies targeting E6/E7	Intracellular inhibition of E6/E7; can deliver cytotoxic payloads	Preclinical	Engineered anti‐E6/E7 nanobodies	Potential for selective targeting, improved intracellular delivery; preclinical only, experimental stage.	[72]

Abbreviations: ACT, adoptive T‐cell therapy; CAR, chimeric antigen receptor T‐cell; CRISPR/Cas9, CRISPR‐associated Cas9 endonucleases; CTL, cytotoxic T lymphocyte; ICB, immune checkpoint blockade; ICIs, immune checkpoint inhibitors; siRNA, small interfering RNA; TALENs, transcription activator‐like effector nucleases; TILs, tumor‐infiltrating lymphocytes; ZFNs, zinc‐finger nucleases.

6. Personalized Medicine for HPV Patients

Personalized medicine for HPV patients is an evolving field focused on tailoring treatment strategies according to individual patient characteristics, including HPV genotype, disease stage, and immune response [10, 104]. Central to this approach is the identification and validation of biomarkers that predict treatment response and help select patients likely to benefit from specific therapies. One widely studied biomarker is PD‐L1 expression on tumor cells, which can predict the efficacy of immune checkpoint inhibitors such as pembrolizumab. Generally, higher PD‐L1 levels correlate with improved therapeutic responses [2, 13]. Similarly, tumor mutational burden (TMB) a measure of the number of mutations within cancer cells may indicate the likelihood of response to immunotherapy, with higher TMB suggesting better outcomes. Another promising tool is circulating tumor DNA (ctDNA) analysis. By detecting tumor‐derived genetic material in the bloodstream, ctDNA profiling provides real‐time insights into tumor characteristics and emerging resistance mechanisms, aiding in the optimization of treatment plans. Treatment selection is also influenced by disease stage. Early‐stage HPV‐related lesions often respond well to minimally invasive interventions, such as excision of precancerous tissue. In contrast, advanced or invasive cancers typically require multimodal treatment approaches, including surgery, radiation, chemotherapy, or combinations thereof. For recurrent or metastatic disease, targeted therapies and immunotherapies are increasingly integrated into personalized treatment regimens, with biomarker‐driven decisions enhancing therapeutic precision [2, 68]. Genetic profiling of the patient can further refine treatment by revealing individual variations in genes related to drug metabolism, immune function, and cancer susceptibility. This information helps predict drug efficacy, potential toxicities, and optimal dosing strategies to maximize benefit and minimize adverse effects [9]. Finally, personalized medicine incorporates lifestyle factors, such as smoking status and diet, which significantly affect treatment response and overall prognosis. Addressing these factors through lifestyle modifications can be an integral part of comprehensive patient management aimed at optimizing clinical outcomes [100, 104].

7. Obstacles

HPV has evolved multiple strategies to evade the host immune system. HPV‐transformed cells can modulate the local immune microenvironment to suppress effective immune responses. These mechanisms include downregulating major histocompatibility complex (MHC) class I expression, impairing antigen processing, and avoiding T‐cell‐mediated cytotoxicity. Additionally, HPV‐infected cells promote immunosuppression by increasing regulatory T cell (Treg) infiltration, secreting immunosuppressive cytokines, inducing immunomodulatory cytokine production from fibroblasts, promoting local innate M2 macrophage polarization, and inducing antigen‐specific Tregs [40, 72, 105]. Such immune evasion contributes to the limited efficacy of immunotherapies, including therapeutic vaccines, in patients with advanced HPV‐related cancers. This is largely attributed to the immunosuppressive tumor microenvironment established by advanced tumors [40, 104]. Moreover, the identification of suitable cancer target antigens remains challenging, as many tumors display poorly characterized antigens, a limited repertoire of cancer‐specific surface markers, and significant interindividual heterogeneity [13]. These factors complicate the development of broadly effective immunotherapeutic strategies. Safety and cost concerns further limit the widespread adoption of certain vaccine platforms, such as mRNA vaccines. Peptide‐based vaccines, while promising, are constrained by MHC restriction, being effective only in individuals with specific human leukocyte antigen (HLA) alleles [106]. Additionally, several therapeutic vaccine modalities including peptide‐ and DNA‐based vaccines exhibit low immunogenicity, necessitating the use of adjuvants to enhance immune responses [38, 100]. Despite their potential, therapeutic vaccines have yet to be integrated into clinical guidelines for HPV infection and cervical precancerous lesions, likely due to the considerable investment required for their development and ongoing challenges related to safety, immunogenicity, HPV genetic diversity, and viral mutagenicity [38, 72, 100, 106]. Fundamentally, a major scientific limitation remains our incomplete understanding of host immune responses to HPV, given that HPV was discovered less than a century ago [72]. Specifically, the effects of mRNA vaccines on CD8 + T cell function within the tumor microenvironment and secondary lymphoid organs remain poorly understood, constraining their broader application in cancer immunotherapy [71, 99].

Despite all the measures outlined above, primary prevention remains the highest priority. Achieving this goal fundamentally depends on the implementation of effective HPV vaccination programs. First ongoing challenges associated with the prevalence and control of HPV, several key strategies have been proposed to overcome barriers and reduce inequities in vaccine access. Potential approaches include implementing national immunization programs and subsidizing the cost of vaccines with broader high‐risk HPV type coverage, particularly in low‐ and middle‐income countries [107, 108].

Integrating HPV vaccination into school‐based health programs alongside other infectious disease prevention measures, and initiating vaccination before the onset of sexual activity, are essential steps. Addressing vaccine hesitancy through culturally tailored educational campaigns and involving trusted healthcare professionals can help counter misinformation and build public confidence [109, 110]. Additional strategies include enhancing provider patient communication to better address concerns and encourage vaccination uptake in the general population, and expanding access to screening by deploying rapid and cost‐effective HPV testing methods in resource‐limited settings. Combining immunotherapies with agents that modulate the tumor microenvironment such as immune checkpoint inhibitors or cytokines may help overcome immune suppression. Further, the development of vaccines tailored to specific HLA types or tumor‐associated antigens could improve immunogenicity and therapeutic effectiveness [111].

Finally, coordinated surveillance of HPV genotypes and vaccine impact, along with sustained investment in research to better understand host immune responses and HPV genetic diversity, will be critical for informing the next generation of vaccines and therapeutic strategies [112].

8. HPV Vaccines

Vaccines against HPV are broadly categorized into two types: prophylactic vaccines and therapeutic vaccines. Prophylactic vaccines have been available since the early 21st century and are designed to prevent HPV infection and its associated diseases. In contrast, therapeutic vaccines are a newer development aimed at treating existing HPV‐related complications.

Several prophylactic HPV vaccines are currently in use: Bivalent Vaccine (Cervarix): Targets HPV types 16 and 18, which are responsible for a large proportion of cervical cancers [11, 113]. Quadrivalent Vaccine (Gardasil): Protects against HPV types 6, 11, 16, and 18. This vaccine guards against cervical cancer (caused by types 16 and 18) and genital warts (caused by types 6 and 11) [36, 114]. Nonavalent Vaccine (Gardasil 9): Covers nine HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58) offering broader protection that includes additional types responsible for about 20% more HPV‐associated cervical cancers [115, 116]. All three vaccines are highly effective at preventing infection and disease caused by the targeted HPV types when administered prior to exposure. Typically, a three‐dose schedule is recommended, though research indicates that two doses can be equally effective in younger individuals [1]. Pre‐licensure clinical trials demonstrated efficacy rates exceeding 90% against HPV infection, genital warts, and high‐grade cervical lesions in women without prior HPV exposure [7]. Real‐world data corroborate these findings, showing substantial reductions in HPV‐related complications following widespread vaccination [115]. Moreover, these vaccines may provide some cross‐protection against non‐targeted HPV types, contributing to an overall decrease in HPV infections. However, as of 2025, only 148 of the 194 WHO member states have incorporated HPV vaccines into their national immunization programs, and the global average coverage for full vaccination among girls aged 9–14 years remains only 47.6% far below the 90% target set for 2030 [117, 118]. HPV vaccines are the cornerstone of cervical cancer prevention, with robust evidence supporting their safety and effectiveness. Nevertheless, global vaccination rates, particularly in low‐resource regions, remain insufficient. Policy interventions such as adopting single‐dose schedules, expanding school‐based vaccine delivery, and investing in public education and local vaccine production are essential to closing the coverage gap and achieving the WHO elimination goals [118]. Also, challenges remain. Vaccination does not protect against all HPV types, and in low‐ and middle‐income countries, the high cost restricts vaccine accessibility. Additionally, prophylactic vaccines offer little benefit to individuals already infected with HPV [39]. Given these limitations, therapeutic vaccines have gained increasing research interest. Though none have yet received FDA approval and many are still in clinical trials, therapeutic vaccines represent a promising new frontier for treating HPV‐related cancers, lesions, and complications [1] (Table 5).

Table 5.

Comparison between prophylactic and therapeutic vaccines.

Features	Prophylactic vaccines	Therapeutic vaccine	Ref.
Mechanism	Stimulate neutralizing antibodies against HPV	Stimulate cell‐mediated immunity against HPV‐infected cells	[2, 119, 120]
Target population	Individuals not yet exposed to HPV	Individuals with existing HPV infections or lesions
Target antigens	L1 surface protein	E6 and E7 oncoproteins
Goal	Prevent initial HPV infection	Treat existing HPV infections and prevent disease progression
Current status	Several FDA‐approved vaccines available	No FDA‐approved vaccines; multiple candidates in clinical trials

9. Future Directions and Challenges

9.1. Advancements

• Vaccination: The introduction of HPV vaccines, including Gardasil and Cervarix, has significantly reduced infections by high‐risk HPV types and lowered cervical cancer incidence worldwide [71].

• Early detection: Enhanced screening techniques such as HPV DNA testing and Pap smears have improved early diagnosis of HPV infections and related cancers, making early intervention more feasible, even in low‐resource settings (51).

• Novel treatments: Ongoing research into targeted therapies and immunotherapies, including monoclonal antibodies and immune checkpoint inhibitors, is expanding therapeutic options for HPV‐related cancers [121].

9.2. Challenges

• Vaccine access: Inequities in vaccine availability and lack of awareness continue to limit vaccination coverage, particularly in low‐ and middle‐income countries [122].

• Misconceptions: Public misinformation and stigma surrounding HPV and its vaccines create barriers to effective prevention and treatment [10].

• Need for continued research: Persistent gaps in understanding HPV's biology, immune evasion, and treatment resistance highlight the necessity for ongoing research to refine and develop more effective prevention and therapeutic approaches [8].

• Ethical and safety considerations

Given the increasing application of gene‐editing technologies and immune‐based therapies, dedicated ethical oversight for advanced biotechnologies such as gene editing and CAR‐T cell therapies has become essential. Ethical and regulatory safeguards must include adherence to established safety principles, rigorous protocol design, independent review, and continuous monitoring throughout clinical research. These measures collectively ensure safety, fairness, and transparency prior to any clinical implementation. Moreover, they protect participants’ rights, uphold scientific integrity, and help maintain public trust in biomedical research [123].

10. Conclusion

HPV research has made remarkable strides, advancing from fundamental understanding of the virus's biology to the development of both preventive and therapeutic interventions. Modern medicine now explores innovative treatment modalities such as immunotherapy, therapeutic vaccines, nanobodies, and gene editing. Despite these significant advancements, challenges persist in ensuring equitable global access to vaccines and treatments, as well as in improving effective screening, treatment, and control of HPV transmission. Continued research, alongside robust public health initiatives, is essential to ultimately eliminate HPV‐associated diseases. This review aims to provide a comprehensive overview of human papillomavirus from its origins to cutting‐edge treatment options while highlighting current gaps in policies and practices surrounding HPV management. Also, Future studies should focus on bridging laboratory discoveries to scalable interventions, particularly in resource‐limited settings. Strengthening vaccine equity and developing affordable molecular diagnostics remain global priorities.

Author Contributions

Fatemeh Beygnejad and Narges Eslami: Investigation, Writing original draft, review and editing, data curation. Kaveh Gharaei Nejad: review and editing, data curation, revision. Atefeh Zamani Kermanshahi: investigation, review and editing. Hossein Bannazadeh Baghi: supervision, conceptualization. All authors have read and approved the final version of the manuscript.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Transparency Statement

The lead author Hossein Bannazadeh Baghi affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Beygnejad F., Eslami N., Nejad K. G., Kermanshahi A. Z., and Baghi H. B., “Human Papillomavirus: Update in Bridging Basic Science to Clinical and Public Health Innovations,” Health Science Reports 9 (2026): e72168, 10.1002/hsr2.72168.

Data Availability Statement

No data was used for the research described in the article.