Comparative studies have consistently revealed distinct microbial signatures in OSCC patients compared to healthy controls (Guerrero-Preston et al., 2016; Zhao et al., 2017; Lyu et al., 2025). Significant shifts in microbial composition are observed as oral mucosa transitions from healthy to precancerous and cancerous states (Lee et al., 2017). For instance, OSCC tissues exhibit a marked depletion of Actinobacteria and Cyanobacteria, along with decreased abundance of Streptococcus, Haemophilus, Porphyromonas, and Actinomyces (Guerrero-Preston et al., 2016; Wei et al., 2025). Conversely, increases in Fusobacterium, Peptostreptococcus, Capnocytophaga, and Alloprevotella are frequently reported in OSCC samples (Zhao et al., 2017; Granato et al., 2021; Lyu et al., 2023). Salivary microbiome analyses also reflect these changes, with notable increases in Prevotella and reductions in Neisseria in cancer patients (Han et al., 2025).

Longitudinal and cross-sectional studies further support these trends. For example, Abiotrophia, Acinetobacter, Peptostreptococcus, and Staphylococcus remain elevated in OSCC patients even after surgical intervention (Soghli et al., 2025). Community-level analyses reveal consistent microbial alterations in the TME, including increased Fusobacteria and Proteobacteria, and decreased Firmicutes and Actinobacteria, with more pronounced changes in metastatic samples (Eun et al., 2021).

Several bacterial species have been implicated in oral carcinogenesis, including both “cross-domain” pathogens found in multiple body sites and oral-specific taxa. F. nucleatum, a well-studied oral pathobiont, is also implicated in colorectal cancer (Gao et al., 2025). It promotes OSCC progression through mechanisms such as epithelial-mesenchymal transition (EMT) via the lncRNA MIR4435−2HG/miR−296−5p/Akt2/SNAI1 pathway and activation of STAT3 (Munoz-Grez et al., 2025). In parallel, Porphyromonas gingivalis (P. gingivalis), Treponema denticola, and Prevotella intermedia are also strongly associated with periodontitis and OSCC. P. gingivalis activates multiple signaling pathways (e.g., ERK1/2-Ets1, p38/HSP27, PAR2/NF−κB) that enhance matrix metalloproteinase expression and tumor invasiveness (Urzica et al., 2025). Both F. nucleatum and P. gingivalis activate the TLR/MyD88-triggered integrin/FAK pathway, further promoting tumor progression (Chen et al., 2018; Liu et al., 2020). In addition, Streptococcus pneumoniae and other Streptococci are also recognized for their pro-inflammatory roles and potential involvement in both oral and systemic carcinogenesis (Su et al., 2021).

Oral dysbiosis contributes to carcinogenesis not only through direct microbial interactions but also via metabolic reprogramming. Shifts in microbial composition, such as increases in Streptococcus, Abiotrophia, and Leuconostoc, and decreases in Prevotella, Haemophilus, and Neisseria, alter the production of short-chain fatty acids (SCFAs), key anti-inflammatory metabolites (Perera et al., 2017). Reduced SCFA levels and downregulation of free fatty acid receptor 2 (FFAR2) expression disrupt immune homeostasis and promote a pro-inflammatory state (Magrin et al., 2020).

Dysbiosis also activates pro-inflammatory pathways such as TNFAIP8 and IL−6/STAT3, which are known to support chronic inflammation and tumor development (Nakkarach et al., 2021). Furthermore, microbial dysbiosis influences the production of other metabolites, including lipoteichoic acid from Streptococci, which perpetuates inflammation and exacerbates mucosal barrier dysfunction (Yau et al., 2018). This metabolic dysregulation, coupled with immune evasion and persistent inflammation, creates a microenvironment conducive to tumor initiation and progression.

The role of microbial metabolites in the progression of OSCC is increasingly evident. A central mechanism in OSCC pathogenesis and immune evasion involves the metabolism of tryptophan through the kynurenine pathway (Lou et al., 2025). In the TME, tryptophan can be converted to kynurenine and downstream metabolites such as kynurenic acid (KYNA), which have been reported to be elevated in OSCC tissues and patient saliva compared with healthy controls, indicating dysregulated tryptophan metabolism in OSCC (Walczak et al., 2020; Zhou et al., 2024).

This metabolic alteration is further driven by specific oral microorganisms, including Streptococcus mutans (S. mutans), which colonizes OSCC tissues and enhances KYNA production via its surface protein antigen C (PAC). The accumulation of KYNA not only disrupts local immune responses but also promotes the expansion of regulatory T cells (Tregs), thereby reinforcing an immunosuppressive TME (Zhou et al., 2024).

Microbial dysbiosis also contributes critically to OSCC progression. The bacteriome in OSCC patients is enriched with pro-inflammatory species such as F. nucleatum and P. aeruginosa, which can influence metabolic pathways including the kynurenine axis (Li et al., 2024, 2025). This promotes an inflammatory microenvironment that exacerbates tissue damage, epithelial proliferation, and tumor development. The altered oral microbiome further facilitates metabolic reprogramming by stimulating the secretion of inflammatory cytokines and metabolites involved in tryptophan degradation, thereby accelerating OSCC progression. At the host level, Tregs in OSCC display pronounced metabolic plasticity, relying on coordinated regulation of glycolysis, fatty acid oxidation, and amino acid metabolism to maintain suppressive function. Activation of the kynurenine–aryl hydrocarbon receptor (AhR) axis has been reported to enhance Treg stability and suppress effector T-cell responses, providing a mechanistic framework by which altered tryptophan metabolism may facilitate immune evasion in OSCC (Kenison et al., 2021; Xu et al., 2023).

In summary, microbial dysbiosis in OSCC not only alters microbial composition but also directly modulates host metabolic pathways, particularly tryptophan metabolism. This interaction between the oral microbiome and host metabolism promotes immune suppression and facilitates tumor immune evasion. From a diagnostic perspective, elevated kynurenine and KYNA levels consistently observed in OSCC tissues and patient saliva indicate that dysregulated tryptophan metabolism may serve as a potential metabolic biomarker of disease presence and immune status. In contrast, therapeutic strategies targeting the kynurenine-AHR axis, including enzyme inhibition or microbiome modulation, remain largely preclinical and are primarily supported by mechanistic and animal studies.

SCFAs such as acetate and propionate are produced by oral microbiota through the fermentation of dietary fibers and resistant starches. SCFAs, in particular, are involved in modulating immune responses in the oral cavity (Baima et al., 2025). These metabolites can influence the balance between pro-inflammatory and anti-inflammatory cytokines. In the context of OSCC, SCFAs can either promote or inhibit cancer progression depending on their concentration and the microbial community’s composition. This interplay suggests that microbial dysbiosis and the subsequent metabolic disturbances contribute to OSCC progression by affecting immune cell infiltration and inflammatory pathways (Nouri et al., 2023).

Among SCFAs, butyrate has received particular attention due to its diverse biological activities (Zang et al., 2022). Notably, physiological butyrate levels in the oral cavity (e.g., saliva/gingival crevicular fluid) are typically far lower than those in the colonic lumen, and this exposure gap should be considered when interpreting dose-dependent dual effects and extrapolating findings across tissues. In many cancer types, including colorectal and lung cancer, butyrate has been classically regarded as a tumor-suppressive metabolite through mechanisms such as HDAC inhibition, activation of G-protein-coupled receptors, and modulation of epithelial and immune cell function (Goncalves and Martel, 2013; Bishoyi et al., 2026). However, emerging evidence in OSCC suggests a more nuanced, context-dependent role in which butyrate can also participate in pro-tumorigenic processes.

The relationship between periodontitis and OSCC is well-documented, with periodontal pathogens such as F. nucleatum and P. gingivalis found to be enriched in OSCC tissues compared to normal tissue (Plottel and Blaser, 2011; Li et al., 2018). Notably, F. nucleatum, a bacterium commonly associated with periodontitis, has been shown to produce butyrate by metabolizing L-glutamate released by OSCC cells. Mechanistically, F. nucleatum upregulates the cystine/glutamate antiporter SLC7A11 in OSCC cells, promoting glutamate efflux and providing a continuous carbon source that can be catabolized into butyrate (Munoz-Grez et al., 2025). This microbial activity not only provides energy to the bacteria but also reshapes the metabolic landscape of the tumor niche, supplying a metabolite that can influence cancer cell growth, stress responses, and interaction with surrounding stromal and immune cells.

Butyrate’s effects on cancer cells are strongly dose and context dependent. Studies in OSCC models have shown that at lower or intermediate concentrations (for example, in the 100–1000 nmol/L range), butyrate can stimulate tumorsphere growth, enhance cellular proliferation, and promote features associated with EMT, including increased migration and invasion (Tsai et al., 2020). Consistent with these findings, butyrate exposure has been reported to upregulate EMT-related markers such as SNAI1, Vimentin, and N-cadherin, while downregulating epithelial markers, thereby facilitating a more invasive phenotype (Du et al., 2014; Zang et al., 2022). In this setting, butyrate may act in concert with other bacterial products (e.g., LPS, proteases) and chronic inflammatory signals to drive matrix remodeling, disrupt cell-cell adhesion, and support local dissemination of OSCC cells. These data support a model in which butyrate derived from dysbiotic periodontal communities can act as a pro-tumorigenic mediator when present at sub-cytotoxic levels in a chronically inflamed microenvironment.

However, the role of butyrate in OSCC progression is not entirely straightforward. While it displays tumor-promoting effects at certain concentrations and in microbiome-driven contexts, its overall impact on cancer progression appears to depend on the balance between these pro-tumoral actions and its intrinsic capacity to function as an HDAC inhibitor and immunomodulatory metabolite (Yue et al., 2022). A substantial body of work indicates that, at higher concentrations or when delivered as a pharmacologic agent, butyrate can inhibit OSCC cell proliferation, induce cell-cycle arrest, and reduce invasive behavior (Zang et al., 2022). Sodium butyrate (NaB), a stable and widely used butyrate derivative, has been shown to suppress OSCC cell growth and invasion by downregulating HDAC1 (Gillenwater et al., 2000). This, in turn, relieves epigenetic repression of the tumor-suppressor gene HSPB7, leading to its upregulation and consequent restriction of OSCC cell survival and motility (Yue et al., 2022). Other studies report that butyrate can decrease the expression of adhesion molecules such as ICAM-1 and modulate inflammatory enzymes like COX-2 and secretory phospholipase A2-X in oral cancer cells, further supporting its potential anti-tumor effects (Gharat et al., 2016).

Furthermore, insights from broader SCFA research suggest that butyrate may also influence OSCC through additional layers of regulation, including effects on angiogenesis, ferroptosis sensitivity, and anti-tumor immunity (Zhong et al., 2025). By inhibiting HDACs and engaging GPCR signaling, butyrate can alter chromatin accessibility, regulate VEGF and its co-receptors, and modulate the activity of T cells, dendritic cells, and NK cells (Bishoyi et al., 2026). Although these mechanisms have been characterized more extensively in other malignancies, they provide a conceptual framework for understanding how butyrate might shape the OSCC TME beyond direct actions on tumor cells, for instance by influencing immune checkpoint signaling or the balance between effector and regulatory immune subsets.

In summary, butyrate, as a microbial metabolite, plays a complex and dual role in OSCC progression. Its presence in the oral cavity, primarily produced by periodontal and other anaerobic bacteria, can contribute to tumor growth and invasion through mechanisms such as EMT induction, metabolic support of pathogenic species like F. nucleatum, and reinforcement of chronic inflammation. At the same time, butyrate retains the potential to exert tumor-suppressive effects via HDAC inhibition, epigenetic reprogramming, and immune modulation, particularly when present at higher concentrations or delivered exogenously. The net effect of butyrate in OSCC thus depends on its local concentration, source (commensal versus pathogenic microbiota), and interaction with host signaling pathways. This duality not only highlights butyrate as a candidate biomarker reflecting dysbiotic metabolic activity in OSCC, but also positions the butyrate axis as a promising, yet challenging, therapeutic target that will require careful tuning of microbiome and metabolite levels to selectively harness its anti-tumor potential.

VSCs, such as methyl mercaptan, are another group of metabolites produced by oral bacteria like P. gingivalis and F. nucleatum (Kwon et al., 2022). These compounds have been implicated in the development of OSCC by promoting an inflammatory microenvironment. VSCs can activate pro-inflammatory cytokine production, leading to immune system dysregulation and chronic inflammation (Krespi et al., 2006). This chronic inflammatory state is a known risk factor for the initiation and progression of OSCC. In addition, VSCs may disrupt epithelial cell barriers, promoting the infiltration of carcinogenic bacteria and enhancing tumor cell proliferation, invasion, and metastasis.

Hydrogen sulfide (H₂S), a VSC, is produced both endogenously and by oral bacteria, playing a significant role in the pathogenesis of oral diseases, including OSCC (Wu et al., 2022). In OSCC, the concentration of H₂S is markedly elevated compared to adjacent benign mucosal tissue, suggesting its involvement in the malignant transformation of oral cells. The enzymes responsible for H₂S synthesis, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfur transferase (3-MST), are upregulated in OSCC tissues, contributing to the increased H₂S levels observed in these malignancies (Meram et al., 2018). This elevation in H₂S concentration correlates with the activation of key oncogenic pathways, such as the MAPK and STAT3 signaling cascades, which are implicated in tumor growth, survival, and metastasis. The presence of H₂S in the OSCC microenvironment also influences the oxidative stress balance, promoting DNA damage and facilitating a pro-inflammatory state conducive to tumor progression (Vitvitsky et al., 2012; Ma et al., 2015; Wu et al., 2022).

Moreover, H₂S-producing bacteria, which thrive in the oral cavity, exacerbate the effects of this gas by increasing its local concentration, further supporting the inflammatory and carcinogenic processes in OSCC (Kwon et al., 2022). The correlation between elevated levels of H₂S and OSCC progression also underscores its potential as a non-invasive diagnostic marker. Studies have shown that exhaled breath analysis, which detects H₂S, could serve as a promising diagnostic tool for OSCC.

In conclusion, H₂S is not only a key microbial metabolite in oral health but also a crucial factor in the pathogenesis of OSCC. Its dual role in promoting oxidative stress, inflammation, and cell survival makes it a potential target for therapeutic intervention in OSCC, as well as a valuable biomarker for early detection of the disease.

Various microbial metabolites produced by oral bacteria also have been shown to influence the inflammatory microenvironment, immune response, and cellular signaling pathways that contribute to cancer progression.

Bacteriocins, antimicrobial peptides produced by beneficial bacteria in the oral microbiota, have also been studied for their potential role in OSCC (Kamarajan et al., 2020). These molecules, produced by species such as Lactobacillus and Streptococcus, have antimicrobial properties that inhibit the growth of pathogenic bacteria like P. gingivalis and F. nucleatum. Since these pathogens are closely associated with OSCC development, bacteriocins might help reduce the pathogenic microbial load, thereby maintaining a healthier microbiome. Some bacteriocins also possess anti-inflammatory properties that may prevent the inflammatory signaling cascades typically observed in OSCC, further suggesting their potential as therapeutic agents.

Secondary bile acids are microbially generated derivatives of primary bile acids; importantly, primary/total bile acids are not produced in the oral cavity but can be detected in saliva mainly due to gastroduodenal reflux (GERD/LPR), which delivers bile-containing refluxate into the upper aerodigestive tract (Krause et al., 2024; Thakur et al., 2025). Accordingly, any discussion of bile acid-oral epithelium interactions should be interpreted as exposure in reflux-associated contexts, and OSCC-relevant evidence remains emerging and largely indirect rather than OSCC-specific causal proof (De Corso et al., 2021). These bile acids can affect various signaling pathways that are dysregulated in cancer, such as the Wnt/β-catenin and JAK-STAT pathways (Akhtar et al., 2025). In particular, certain secondary bile acids have been linked to increased carcinogenesis by promoting DNA damage and mutations in oral epithelial cells. The role of these metabolites in OSCC depends heavily on the balance between beneficial and pathogenic microbes in the oral cavity (Abusleme et al., 2013). Dysbiosis, marked by an overabundance of certain bacteria that produce harmful secondary bile acids, could increase the risk of cancer development.

Beyond established microbial metabolites, lactate is emerging as a key player that actively remodels the tumor microenvironment, representing a potentially overlooked node within the oral “microbiome-metabolite-host” axis (Gong et al., 2026). In cancer, heightened aerobic glycolysis (the Warburg effect) leads to lactate accumulation within tumors (Hanahan and Weinberg, 2011). Rather than a mere metabolic waste product, lactate is now recognized as a pleiotropic signaling molecule implicated in disease progression. It serves as both a readout of cellular metabolic activity and a driver that reinforces glycolytic flux through feedforward metabolic-transcriptional coupling. Mechanistically, lactate shuttling between cells-mediated by monocarboxylate transporters (MCT1-MCT4)-allows it to function as an energy substrate and, importantly, as a signaling messenger that coordinates metabolic crosstalk in the tumor niche (Singh et al., 2023). Notably, lactate-induced protein and histone lactylation provides a direct link between metabolism and epigenetic regulation, contributing to immunosuppressive reprogramming, such as promoting M2-like macrophage polarization and recruiting tumor-associated macrophages via the STAT3-CCL2 axis (Sun et al., 2025). In head and neck squamous cell carcinoma, elevated histone lactylation (e.g., H3K9la) has been associated with poorer responses to immunotherapy, highlighting its potential translational relevance in OSCC (Gong et al., 2026). Collectively, these insights argue for incorporating lactate and lactylation into the metabolic landscape of OSCC. Future studies should clarify the relative contributions of host- versus microbiota-derived lactate pools and define context-dependent thresholds that dictate whether lactate exerts pro-tumor or immunomodulatory effects.

Acetaldehyde (ACH) serves as a prototypical microbial, chemical effector that bridges conventional risk factors such as alcohol and smoking to local carcinogenic metabolism in the oral cavity. Ethanol is oxidized to acetaldehyde by oral microorganisms via microbial alcohol dehydrogenase activity, with a wide range of taxa, including oral streptococci, Neisseria spp., and Candida, capable of generating substantial acetaldehyde under physiologically relevant ethanol exposure (Marttila et al., 2013; Naz and Zafar, 2025). Culture-based studies using site-specific isolates from OSCC lesions, oral lichenoid lesions, and healthy mucosa have demonstrated that many of these microbes frequently produce mutagenic concentrations of acetaldehyde, with elevated levels observed particularly in smokers (Marttila et al., 2013). This supports a model of microbial ecological selection under chronic exposure. Mechanistically, acetaldehyde acts as a direct chemical carcinogen by forming DNA adducts and crosslinks, impairing DNA synthesis and repair. In OSCC tissues, microbial acetaldehyde production correlates with suprabasal p53 immunostaining, aligning with documented TP53 mutagenesis in adjacent epithelia driven by acetaldehyde exposure (Marttila et al., 2021). Notably, oral leukoplakia is a key oral potentially malignant disorder that exhibits enrichment of taxa previously linked to acetaldehyde generation (e.g., Rothia mucilaginosa, Streptococcus parasanguinis, Streptococcus salivarius), further supporting the role of acetaldehyde as a functional metabolic axis active early in malignant transformation (Ramos et al., 2020; Galvin et al., 2025).

Polyamines, such as putrescine, spermidine, and spermine, are small cationic metabolites that can be synthesized within oral biofilms and often accumulate in tumors. In bacteria, putrescine is typically generated from arginine or ornithine through decarboxylation pathways. For example, S. mutans employs the agmatine deiminase system to convert agmatine (derived from arginine) into putrescine. Additionally, F. nucleatum has been shown to stimulate putrescine production, indicating a likely microbial origin of polyamines in dysbiotic oral environments (Zhi et al., 2024). In OSCC, polyamine metabolism is commonly upregulated: malignant epithelial regions exhibit elevated levels of spermidine or spermine, along with heightened activity of key biosynthetic enzymes (ODC1-SRM-SMS), in line with the established roles of polyamines in supporting cellular proliferation and remodeling the tumor microenvironment (Tang et al., 2023).

Taken together, these microbial metabolites, SCFAs, VSCs, bacteriocins, and secondary bile acids, etc., illustrate the complex relationship between the oral microbiota and OSCC. Dysbiosis, or an imbalance in microbial populations, can lead to a shift in metabolite production that promotes carcinogenesis through inflammation, immune modulation, and cellular damage. Further research into these metabolites may provide novel therapeutic approaches for managing OSCC by targeting microbial pathways or manipulating the oral microbiome to restore a healthy balance.

The identification of microbial metabolites in saliva or tissue metabolic profiles has emerged as a promising strategy for the early diagnosis of OSCC and the prediction of malignant transformation risk. Specific metabolites and their ratios in the oral environment can serve as potential biomarkers for OSCC detection. For instance, the elevated levels of KYNA and the ratio of certain SCFAs, such as acetate, propionate, and butyrate, have been linked to OSCC development (Zhou et al., 2024). The balance between beneficial and pathogenic microbiota is reflected in these metabolic signatures, providing insights into cancer progression (Duan et al., 2025). Furthermore, H₂S, a metabolite produced by oral bacteria, has shown potential as a biomarker for OSCC, with altered levels correlating to cancerous changes in the oral mucosa. These metabolic profiles can be utilized in non-invasive diagnostics, such as saliva-based tests, to detect OSCC at early stages or predict the risk of malignant transformation in premalignant lesions (Wu et al., 2022).

Microbial metabolites not only hold potential as biomarkers but also present novel therapeutic targets for OSCC treatment. The targeting of specific metabolic enzymes and receptors could offer a way to halt or slow OSCC progression.