From dysbiosis to tumor progression: the microbiome's role in head and neck squamous cell carcinoma (HNSCC)

 Corresponding author: Dr. Anshika Srivastava Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. From dysbiosis to tumor progression: the microbiome’s role in head and neck squamous cell carcinoma (HNSCC) Anshika Srivastava , Bhavika Sain, Abhilasha Fenin, Ashmeen Kaur and Aarohi Punj Department of Oral Pathology, Adesh Institute of Dental Sciences & Research, Bathinda-151001, Punjab, India. World Journal of Advanced Research and Reviews, 2025, 26(02), 2555-2562 Publication history: Received on 30 March 2025; revised on 14 May 2025; accepted on 17 May 2025 Article DOI: https://doi.org/10.30574/wjarr.2025.26.2.1782 Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the leading health issues globally. Oral cavity harbors a rich variety of microbes, which are in charge of preserving homeostasis under healthy circumstances. Imbalance among this microbial community—is referred to as oral dysbiosis—that has the potential to cause oncogenesis by chronic inflammation, immune modulation, and genotoxic effect. Pathogenic bacteria, including Porphyromonas gingivalis, Fusobacterium nucleatum and Treponema denticola have been linked with the development & progression of tumors. Dysbiotic microenvironment is capable of causing DNA damage, inducing epithelial-mesenchymal transition, and remodeling the tumor microenvironment, hence facilitating cancer development and progression. The current review aims at tackling the multifaceted relationship between oral dysbiosis and head and neck squamous cell carcinoma (HNSCC) in light of underlying molecular mechanisms, potential diagnostic application and therapeutic measures. Keywords: Oral cavity; Squamous cell carcinoma; Oral dysbiosis; Carcinogenic; Tumor; Porphyromonas gingivalis; Fusobacterium nucleatum; Tumor microenvironment; Oncogenesis 1. Introduction Head and neck squamous cell cancer (HNSCC) ranks amongst the most frequent malignant malignancies of the head & neck [1], qualifying it to become a prime universal health focus area. This life-threatening cancer has bleak prospects when treated with advanced generations of radiochemotherapy treatments; therefore, there is a need for early recognition with intensified efforts towards therapeutic treatment [2]. Risk factors such as tobacco use, alcohol consumption, and infection with human papillomavirus (HPV) are established, but there is emerging evidence to support the involvement of the oral microbiome in carcinogenesis [3]. The human oral cavity contains a rich microbial community that includes bacteria, fungi, viruses, and archaea and is essential in ensuring oral and systemic health [4]. Under healthy states, commensal bacteria like Streptococcus and Veillonella play roles in immune homeostasis and pathogen resistance. Yet, alterations in microbial balance—also known as oral dysbiosis—can result in chronic inflammation, immune evasion, and tumor-promoting actions [5]. Interestingly, opportunistic pathogens like Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola have been shown to promote oncogenic pathways through immune modulation, bacterial metabolites, and genotoxic effects [6]. Some recent studies indicate that oral microbial dysbiosis can be both a biomarker and a target for therapeutic intervention for HNSCC [7]. Elucidating the tumor-microbiome relationship is pivotal to the development of precision oncology. In this review, the complex interaction between oral dysbiosis and HNSCC is discussed, highlighting carcinogenesis mechanisms, diagnostic, and novel therapeutic approaches. World Journal of Advanced Research and Reviews, 2025, 26(02), 2555-2562 2556 2. Oral microbiome The oral cavity shelters a dynamic and multifaceted microbial community consisting of more than 700 species of bacteria, in addition to fungi, viruses, and archaea [8]. This microbial community is vital to both oral and systemic health, as it monitors immune responses, inhibits colonization by pathogenic microbes, and contributes to vital metabolic processes [9]. Oral homeostasis depends on a balanced oral microbiome, but microbial composition disturbances—oral dysbiosis—can cause a number of diseases, such as periodontitis and caries, and possibly head and neck squamous cell carcinoma (HNSCC) [10]. 2.1. Composition of the Oral Microbiome The oral microbiota comprises commensal and pathogenic microbes that are in harmony with the host in a finely tuned balance. Commensal bacteria like Streptococcus, Veillonella, Rothia, and Neisseria, which play roles in immune modulation and preventing pathogen overgrowth [9], are mostly found in healthy individuals. They serve to maintain oral pH, break down dietary constituents, and communicate with the immune system to modulate inflammatory processes [11]. Dysbiosis, on the other hand, involves an accumulation of pathogenic species such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola—microbes that are well known for their involvement in periodontitis and, more recently, in carcinogenesis [12]. They play roles in immune evasion, chronic inflammation, and the production of oncogenic metabolites [6]. 2.2. The Microbiome’s Role in Immune Homeostasis The oral microbiome is also important in modulating immune responses. Immune system activity is controlled by commensal bacteria through the stimulation of pattern recognition receptors (PRRs), e.g., Toll-like receptors (TLRs), to ensure immune homeostasis [13]. Immune tolerance is enhanced by a healthy microbiome through cytokine regulation, including interleukin-10 (IL-10), which is anti-inflammatory [14]. On the other hand, oral dysbiosis may interfere with immune regulation to induce a pro-inflammatory condition with increased levels of tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6), and interleukin-8 (IL-8)—all of which play a role in tumor growth [15]. Bacterial dysbiosisinduced chronic inflammation could be responsible for the development of a microenvironment favouring carcinogenesis, facilitating malignant transformation of the oral epithelium [16]. 2.3. Dysbiosis as a Disease Precursor Oral dysbiosis is long established in periodontal disease and caries, but growing evidence indicates that it plays a role in systemic diseases such as cardiovascular disease, diabetes, and even neurodegenerative disorders [17]. Of particular interest, recent evidence has shown that microbial dysbiosis has a strong association with the development of HNSCC, and it is proposed that certain bacterial communities may play a role in cancer initiation and progression [18]. For example, F. nucleatum—a periodontitis-associated bacterium—has been found to induce epithelial-mesenchymal transition (EMT), facilitate immune evasion, and enhance resistance to apoptosis in cancer cells [19]. Likewise, P. gingivalis can cause DNA damage and suppress normal repair mechanisms of epithelial cells, further aiding carcinogenesis [20]. These data indicate that preservation of oral microbial homeostasis is not merely critical for avoidance of periodontal disease but potentially also holds relevance for prevention of cancer. Further elucidation of the function of the microbiome in the regulation of the immune system and disease development can open the way for new diagnostics and therapies aiming at microbial dysbiosis. 3. Oral dysbiosis and carcinogenesis There have been numerous studies performed in recent times to ascertain the connection between oral dysbiosis and carcinogenesis that drew monumental attention [21]. Oro-pathogens can manipulate the tumor microenvironment by several ways, i.e., chronic inflammation, immunosuppression, bacterial metabolism, and genotoxicity directly [22]. These processes grant a supporting niche for the malignant transformation [23]. World Journal of Advanced Research and Reviews, 2025, 26(02), 2555-2562 2557 3.1. Mechanisms linking dysbiosis to HNSCC 3.1.1. Chronic Inflammation and Carcinogenesis Inflammation is a body’s natural procedure which occurs in response to any infection or injury to promote better & faster healing . It can be acute or chronic. Chronic inflammation is well-established hallmark of cancer [24]. P. gingivalis and F. nucleatum trigger the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, leading to production of pro-inflammatory cytokines i.e. interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-8 (IL-8) [25]. Inflammation lasting for longer duration produces reactive oxygen & nitrogen species (ROS & RNS), inducing DNA damage, genomic instability, and epigenetic modifications— which are the primary events in carcinogenesis [24]. 3.1.2. Microbial Metabolites and Oncogenesis Oral bacteria yield metabolites that may contribute to oncogenesis. For instance, some anaerobic bacteria, for instance, F. nucleatum and P. gingivalis, produce short-chain fatty acids (SCFAs) like butyrate and propionate, which could compromise epithelial cell integrity and amplify tumor-promoting pathways [25]. Moreover, nitrosamine formation by Neisseria and Haemophilus species is of specific interest. Nitrosamines are established carcinogens that result in DNA alkylation, mutagenesis, and enhanced oxidative stress, which play a role in malignant transformation [26]. 3.1.3. Immune Evasion and Tumor Progression Evasion of immune surveillance is one of the characteristics of cancer. Evasion occurs through mechanisms that have been developed by certain oral pathogens so that they may inhibit immune function and thus shield tumor cells from being detected. P. gingivalis, for instance, inhibits apoptosis of infected epithelial cells by interfering with Bcl-2 family proteins and thus allows long-term survival of transformed cells [27]. Moreover, F. nucleatum is found to interact with Toll-like receptors (TLRs) and β-catenin signaling, suppressing T-cell responses and promoting immune evasion [28]. Interactions like this result in uncontrollable cancer cell growth. 3.1.4. Genotoxic Effects and DNA Damage Several oral pathogens produce a chemical named genotoxin which is responsible for causing DNA damage and genomic instability. For instance, P. gingivalis produces gingipains, a class of proteases that degrade host proteins and facilitate mutagenic changes [29]. Similarly, F. nucleatum has been linked to double-strand DNA breaks, which promote chromosomal instability—a key feature of cancer progression [3]. 4. The microbiome-tumor microenvironment interplay in HNSCC The tumor microenvironment (TME) plays a crucial role in cancer progression, influencing tumor cell proliferation, immune evasion, and therapeutic resistance. Several studies indicate that oral microbiota has the potential to shape the TME in HNSCC by modulating the inflammatory pathways, metabolic interactions & immune responses [30]. 4.1. Inflammation-Driven Tumor Microenvironment Persistent inflammation is one of the characteristics of the microenvironment of HNSCC, and oral pathogens play an active role in this inflammatory process. Porphyromonas gingivalis and Fusobacterium nucleatum cause chronic inflammatory signaling through the activation of the nuclear factor kappa B (NF-κB) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways [24]. These pathways result in increased pro-inflammatory cytokines like: • Tumor necrosis factor-alpha (TNF-α) – It promotes angiogenesis and survival of tumor cell. • Interleukin-6 (IL-6) and Interleukin-8 (IL-8) – Responsible for cancer cell proliferation and invasion. • Transforming growth factor-beta (TGF-β) – Promotes epithelial-mesenchymal transition (EMT), facilitating metastasis [15]. 4.2. Immunosuppressive Effects of Dysbiosis The immune response is key to managing tumor growth, but oral pathogens have the ability to establish an immunosuppressive microenvironment supporting cancer growth (see figure 1 ) [13]. World Journal of Advanced Research and Reviews, 2025, 26(02), 2555-2562 2558 Figure 1 Flowchart representing the immunosuppressive effects caused by oral dysbiosis The interplay of chronic inflammation, immune suppression, and checkpoint activation establishes a tumor - permissive microenvironment, making HNSCC resistant to immune-mediated clearance. 4.3. Microbial Metabolites and Tumor Metabolism Oncogenic metabolites are produced by the oral pathogens to sustain the tumor growth. Metabolites like short chain fatty acids (SCFAs), polyamines & bacterial lipopolysaccharides (LPS) play an important role. These metabolic interactions underscore the ways in which oral microbiota affect tumor growth independent of direct infection, pointing to new directions for metabolic-targeted therapies in HNSCC treatment. Short chain fatty acids (SCFAs) like butyrate and propionate may play bivalent roles—both tumor suppressors during normalcy and tumor promoters during dysbiosis [31]. Polyamines like putrescine and spermidine from P. gingivalis promote cancer cell growth and apoptosis resistance [32]. Bacterial lipopolysaccharides (LPS) stimulate Toll-like receptors (TLRs) on immune and tumor cells, promoting tumor-facilitating inflammation [33]. 4.4. Biofilms and Their Role in Tumor Aggressiveness Biofilms are communities of microbes that are enclosed in an extracellular matrix. It acts as a “protective covering”for the encased microbes preventing them from harsh environment [34]. Biofilm bacteria produce a pro-tumorigenic niche through: • Increased resistance to chemotherapy by elevated extracellular matrix production, which hinders drug penetration[35]. • Inducing epithelial-mesenchymal transition (EMT) and tumor invasion [35]. • Creating hypoxic conditions, resulting in vascularization and tumor growth [35]. Targeting biofilms by anti-biofilm agents or interfering with bacterial communication (quorum sensing inhibitors) is a new approach in microbiome-targeted cancer treatment. 5. The role of the microbiome in treatment response and resistance in HNSCC The oral microbiome's composition has increasingly been understood as a critical determinant of treatment efficacy and resistance in head and neck squamous cell carcinoma (HNSCC). Dysbiosis can affect the effectiveness of World Journal of Advanced Research and Reviews, 2025, 26(02), 2555-2562 2559 radiotherapy, chemotherapy, immunotherapy, and targeted therapies, influencing outcomes for patients. Exploring the role of the microbiome in therapeutic resistance may unlock new possibilities for personalized therapy strategies in HNSCC [7]. 5.1. Microbiome and radiotherapy response 5.1.1. Microbial Modulation of Radiation Sensitivity The bacterial ecosystem in the oral cavity can be easily altered by radiation, resulting in increased level of pathogenic microbes. These bacteria are involved in inflammation and delayed mucosal healing, impairing treatment compliance and patient outcome. On the other hand, some commensal bacteria (Streptococcus and Lactobacillus spp.) have radioprotective properties, which indicate that modulation of the microbiome may prevent mucositis severity [6]. 5.1.2. Microbiome-Induced Radioresistance P. gingivalis and Treponema denticola stimulate DNA damage repair mechanisms, ensuring tumor cell survival after radiation [10]. Moreover, tumor hypoxia, which is caused by the microbiota, also leads to radioresistance because hypoxic tumor cells are less sensitive to ionizing radiation [3]. Efficient strategies specifically targeting the microbes are probiotics & antibiotics to downgrade the level of bacterial population & enhance radiotherapy efficacy. 5.2. Chemotherapy and microbiome interactions Chemotherapeutic drugs, such as cisplatin and 5-fluorouracil (5-FU) are widely used in the treatment of HNSCC. Nevertheless, the oral microbiome impacts drug metabolism, activity, and toxicity considerably. 5.2.1. Microbial Metabolism of Chemotherapeutic Agents Microbial enzymes are known to modify metabolism of chemotherapy drugs, thereby altering drug effectiveness. For example, Enterococcus faecalis inactivates 5-FU, blunting its cytotoxic effect [17]. P. gingivalis is also known to trigger drug efflux pumps within cancer cells, reducing intracellular drug levels and leading to chemoresistance [11]. 5.2.2. Microbiome Impact on Toxicity of Chemotherapy Chemotherapy-induced oral mucositis is aggravated by microbiome dysbiosis, which results in an overgrowth of opportunistic pathogens that extend inflammation and raise secondary infections [36]. Microbiome modulation procedures like prebiotics and probiotics can mitigate mucositis and enhance chemotherapy tolerance [37]. In addition, new interventions like microbial engineering and dietary adjustments have potential in eradicating bacteria involved in chemoresistance. 6. Immunotherapy: the microbiome as a predictor of response Immunotherapy & immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 in particular, has revolutionized HNSCC treatment. Yet, the microbiome is an important determinant of response rates. 6.1. Microbiome Composition and Immunotherapy Response Patients with a more diverse richness of commensal bacteria (Lactobacillus and Bifidobacterium spp.) have greater reactions to PD-1 inhibitors [7]. On the other hand, immune evasion and ICIs resistance is linked with pro-inflammatory species F. nucleatum and P. gingivalis [38]. 6.2. Microbiome-Mediated Immune Modulation Some bacterial metabolites, including short-chain fatty acids (SCFAs), modulate T-cell function and anti-tumor immune responses [39]. F. nucleatum also inhibits cytotoxic CD8+ T-cell function, weakening the effectiveness of immune checkpoint blockade [10]. 6.3. Microbiome-Immune Therapy Synergy Microbiome-directed treatments, such as fecal microbiota transplantation (FMT) and microbiome therapeutics, are being investigated to augment immunotherapy effectiveness [17]. Clinical trials have shown that patients who receive microbiome-modulating therapies in combination with ICIs have better survival rates. World Journal of Advanced Research and Reviews, 2025, 26(02), 2555-2562 2560 7. Microbiome-based therapeutic strategies in HNSCC As more evidence converges linking the dysbiosis of oral microbiome with HNSCC disease progression and chemoresistance, scientists are venturing to understand microbiome-manipulating therapeutic approaches for a better response in treatment. Several methods such as probiotics, prebiotics, antibiotics, bacteriophage therapy, transplantation of microbiota, and engineering of the microbiome have stepped forward as efficient adjuncts with traditional anticancer therapies. Probiotics and Prebiotics are important in restoring the balance of microbes and enhancing immune response. There are beneficial strains of bacteria like Lactobacillus and Bifidobacterium, which have shown promise in inhibiting cancerrelated pathogenic bacteria. Probiotics reduce inflammation, boost immunity in the gut and the mouth, and enhance overall treatment outcomes [40]. Prebiotics like dietary fiber and polyphenols feed the above-mentioned beneficial bacteria and help increase the healthy composition of the microbiome [41]. Research indicates that the addition of probiotic supplementation may alleviate mucositis induced by treatment and lower chemoradiotherapy complications [12]. Selective Antibiotic Therapy and Bacteriophage Treatment are also being investigated as precision-based methods to kill cancer-related bacteria without harming useful microbial communities. Pathogenic genera like Porphyromonas gingivalis and Fusobacterium nucleatum have been linked to tumor growth and immune suppression. It may be possible to decrease chemoresistance and increase the efficacy of immunotherapy by targeting these bacteria with narrowspectrum antibiotics or bacteriophage therapy, which employs viruses to selectively destroy harmful bacteria. But selection must be done cautiously to prevent destabilizing the entire microbiome and thus potentially interfering with immune function and treatment efficacy [17]. Microbiota Transplantation has been in the spotlight as a promising approach to maximize the immune environment for cancer treatment. Fecal microbiota transplantation (FMT), where healthy gut microbiota are transplanted to regain microbial homeostasis, was found to be promising in enhancing response to immune checkpoint inhibitors in cancers like melanoma. In consideration of the robust relationship between gut and oral microbiomes, transplantation of oral microbiota (OMT) has been proposed for its efficacy to alter HNSCC-related tumor-associated dysbiosis. Through this measure, it has been suggested, enhanced immunotherapy rates, decrease in inflammatory cytokines, and better tumor microenvironment can be enhanced. Microbiome Engineering and Metabolite-Based Therapies are novel strategies that utilize bacterial alterations for therapeutic intervention. Scientists are investigating the potential of genetically engineered commensal bacteria to target anticancer compounds directly to the tumor. Moreover, microbial metabolites, including short-chain fatty acids (SCFAs) and polyamines, have been recognized as crucial regulators of tumor growth and immune responses. In general, incorporating microbiome-targeted therapies into HNSCC treatment regimens has the potential to transform cancer therapy. Reducing resistance to treatment, stimulating immune function, and minimizing adverse effects, these approaches hold much promise for customized cancer therapy. Yet, more clinical trials must be conducted to demonstrate the safety, effectiveness, and long-term consequences of microbiome-based treatments. With advancing insights into the connection between the tumor and microbiome, the use of microbiome modulation could become a fundamental aspect of precision oncology for HNSCC patients. 8. Conclusion Any oral or systemic illness develops based on the importance of oral microbiomes. The interactive relationship between oral microbiome functions as a significant indicator toward developing microbiome-based precise cancer therapy for HNSCC patients. The recognition of microbial treatment responses enables clinicians to develop improved treatment interventions that generate superior patient results. Future medical research should dedicate its efforts to integrated therapeutic approaches which focus on oral microbiome interventions through probiotic treatments, microbiome transplanted therapies, and bacterial inhibition methods into standard HNSCC clinical care. Better knowledge about these interactions will be vital for optimizing therapy efficacy while minimizing resistance to ensure improved survival rates. World Journal of Advanced Research and Reviews, 2025, 26(02), 2555-2562 2561 Compliance with ethical standards Disclosure of conflict of interest The author declare that there is no potential conflict of interest with respect to the authorship and/or publication of this article. References [1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. 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