The role of oral microbiota in lung carcinogenesis through the oral-lung axis: a comprehensive review of mechanisms and therapeutic potential

Abstract

Purpose

Growing evidence highlights the crucial role of microbial communities in tumorigenesis across various organs. As the primary gateway for microbial entry into the human body, the oral cavity harbors a complex microbiome that may significantly influence systemic health, particularly pulmonary conditions. Notably, studies reveal remarkable similarities between oral and lung microbial compositions in healthy individuals, suggesting potential crosstalk through the oral-lung axis that could impact lung tumor development. However, the precise mechanisms by which oral microbiota contribute to pulmonary carcinogenesis remain poorly understood. Understanding the relationship between oral microbes and lung tumors is important for the prevention and treatment of diseases such as lung cancer.

Methods

This review systematically synthesizes the latest research advances on the association between oral microbiota and lung cancer. It first elucidates the evidence demonstrating how oral microbiota promote lung carcinogenesis through the oral-lung axis, then dissects the underlying molecular mechanisms through three key dimensions: microbial metabolites, chronic inflammation, and immune regulation. Finally, it discusses potential microbiota-targeted therapeutic strategies.

Results

Emerging evidence establishes the oral microbiome as a key modulator of lung carcinogenesis through the oral-lung axis. Specifically, pathogens like Porphyromonas gingivalis and commensals such as Veillonella and Prevotella promote tumor progression through multiple mechanisms, including metabolite secretion, chronic inflammation induction, and immunosuppression. Furthermore, smoking exacerbates this process by significantly disrupting microbial homeostasis. Regarding therapeutic approaches, current strategies—particularly probiotics, polyphenol-rich diets, professional oral care, and phytomedicines like berberine—show considerable promise. However, these interventions still require further mechanistic validation through rigorous preclinical and clinical studies.

Conclusion

The oral microbiota promotes the occurrence and development of lung cancer through the oral and pulmonary axis through multiple mechanisms such as metabolite secretion, chronic inflammation induction and immunosuppression, and smoking significantly exacerbates this process by disrupting microbial homeostasis. The therapeutic effect has been preliminarily confirmed by antimicrobial therapy and probiotic intervention.

Background

The oral cavity serves as a critical gateway for both the digestive and respiratory systems, playing a pivotal role in maintaining overall health. According to the World Health Organization (WHO), oral health is defined by the absence of dental caries, pain, or gingival bleeding, along with clean teeth and normal gum coloration. It is recognized as one of the ten essential indicators of human health. The oral microecosystem is a highly complex and dynamic environment comprising diverse microbial communities, host anatomical structures (teeth, periodontium, tongue, and oral mucosa), and salivary components [1]. These elements interact intricately, shaping a unique microbial ecosystem. The composition of the oral microbiome varies significantly among individuals due to factors such as diet, oral hygiene, genetic predisposition, and lifestyle habits (e.g., smoking, sugar consumption, antibiotic use, and vaccination). Currently, the expanded Human Oral Microbiome Database (eHOMD 3.1) catalogs 774 oral bacterial species, of which 58% are formally named, 16% are cultured but unnamed, and 26% remain uncultured. In healthy individuals, the predominant phyla include Bacteroidetes and Firmicutes, with key genera such as Prevotella, Veillonella, and Streptococcus [2–4].

Dysbiosis of the oral microbiome has been implicated in local pathologies, including dental caries, periodontal disease, and oral candidiasis [5]. Moreover, emerging evidence highlights a bidirectional relationship between oral and systemic diseases. For instance, periodontal disease and dental caries may contribute to systemic conditions such as cardiovascular disease, diabetes, adverse pregnancy outcomes, cognitive decline, and cancer. Conversely, systemic diseases like diabetes, HIV/AIDS, and hematologic disorders often manifest with oral complications.

A growing body of evidence suggests that the oral microbiome may directly influence pulmonary health. Anatomically contiguous and frequently exposed to aspirated oral secretions, the lungs harbor a microbiome that closely mirrors the oral cavity in healthy individuals, albeit with lower biomass [6–8]. This overlap is attributed to microaspiration or mucosal migration, positioning the oral microbiome as a primary source of lung microbial colonization [9–11]. The oral microbiota and lung tissue homeostasis through direct microbial translocation via aspiration/inhalation, systemic dissemination of inflammatory mediators, and immune modulation mediated by the gut-lung axis maintain dynamic interactions. When disrupted by factors such as smoking, immunosuppression, or chronic inflammation, oral dysbiosis (characterized by overgrowth of pathogens like Porphyromonas gingivalis and imbalance of commensals such as Veillonella) can induce chronic inflammation and compromise epithelial barrier function through the release of virulence factors and metabolites, ultimately promoting lung carcinogenesis [12]. LC remains the leading cause of cancer-related deaths globally. While 80% of cases are smoking-associated, 20–25% occur in lifelong non-smokers, with etiology poorly understood [13]. Intriguingly, recent studies reveal distinct oral microbiome signatures in LC patients versus healthy controls, independent of smoking status. For example, elevated Capnocytophaga and Veillonella in oral samples correlate with LC risk, while Streptococcus may exert protective effects [14, 15]. These observations raise pivotal questions: Could oral microbial dysbiosis directly promote pulmonary carcinogenesis through chronic inflammation or genotoxin production? Alternatively, might it serve as an early biomarker for LC detection?

This review aims to synthesize current evidence on the association between the oral microbiome and lung cancer, with a focus on characterizing microbial differences between patients and healthy controls. By elucidating these relationships, we seek to provide novel insights for advancing diagnostic, prognostic, and therapeutic strategies, ultimately contributing to more effective lung cancer prevention and management.

Methodology

We conducted a comprehensive literature search across four electronic databases: PubMed, Embase, Web of Science, and Cochrane Library. The search employed the following key terms: “oral microbiota”, “Periodontal pathogens”, “lung cancer”, “Microbial metabolism”, “oral-lung axis” and “microbiome carcinogenesis” to identify studies investigating the association between oral microbiota and pulmonary malignancies. The selected publications incorporated in this research should satisfy these specific requirements: (1) Explicit description of crosstalk between oral microbiota and either respiratory diseases or lung cancer. (2) Availability of complete, reliable, and accessible conclusions or experimental results. Publications will be excluded under these circumstances: (1) Contained incomplete, inaccessible, or inconclusive data. (2) Were published in languages other than English.

Literature review

Normal respiratory flora

The traditional view of the healthy lung as a sterile environment has been fundamentally revised, with current evidence demonstrating the presence of diverse microbial communities throughout both healthy and diseased respiratory systems. Modern microbiome research reveals that distinct microbial ecosystems exist across the upper and lower respiratory tracts, each exhibiting unique alpha and beta diversity patterns [16]. These microbial communities—comprising bacteria, fungi, and viruses—form complex ecological networks that vary by anatomical niche.

Comprehensive characterization of the lung microbiome requires examination of all microbial domains: bacteriome, mycobiome, and virome. Notably, human papillomavirus (HPV), particularly high-risk genotypes 16 and 18, shows significant associations with lung squamous cell carcinoma, demonstrating geographical variation in prevalence [17]. While viral and fungal components of the oral microbiome remain understudied, bacterial communities have been more thoroughly characterized.

Comparative analyses reveal striking similarities between oral and lung microbiomes, suggesting a potential migratory pathway. In contrast, nasal microbial communities demonstrate less similarity to lung ecosystems. The nasal cavity and nasopharynx are typically dominated by Moraxella, Staphylococcus, Corynebacterium, Haemophilus, and Streptococcus species. The oropharynx shows distinct colonization patterns, with a predominance of Prevotella, Veillonella, Streptococcus, Fusobacterium, Rothia, Neisseria, and Haemophilus species [18]. The trachea and lungs maintain comparatively lower microbial biomass, primarily composed of Prevotella, Streptococcus, and Veillonella species. These commensal organisms are increasingly recognized for their potential protective roles in respiratory health. The observed continuity between oral and pulmonary microbiota supports the hypothesis of microbial translocation along the respiratory tract, with important implications for understanding respiratory disease pathogenesis [19].

Pulmonary cellular responses to oral microbiota dysbiosis

The pulmonary response to oral microbiota dysbiosis exhibits temporally dynamic and spatially heterogeneous characteristics: the upper respiratory tract primarily relies on mechanical clearance and innate immunity, whereas the lower respiratory tract predominantly depends on adaptive immune regulation. During the initial defensive phase (0–72 h), coordinated actions between ciliary clearance and surfactant protein D (SP-D)-mediated microbial recognition trigger TLR4/NF-κB pathway activation, inducing alveolar macrophages to secrete IL-1β [20]. The intermediate regulatory phase (72 h-4 weeks) is dominated by adaptive immunity, featuring CCL20-CCR6 axis-mediated dendritic cell migration that drives Th17 cell expansion [21], accompanied by significantly enhanced IgA class-switching efficiency in bronchus-associated lymphoid tissue [22]. In the chronic pathological phase (> 4 weeks), persistent activation of Notch and TGF-β/Smad pathways leads to goblet cell metaplasia and myofibroblast transdifferentiation [23]. Emerging evidence demonstrates that microbial metabolites (e.g., short-chain fatty acids) can modulate gene expression profiles in pulmonary epithelial cells through epigenetic modifications [24], providing a novel theoretical framework for understanding microbe-host interactions.

Lung cancer and oral flora

The oral cavity represents one of the most complex microbial ecosystems in the human body, harboring diverse bacterial, viral, and fungal communities. Growing evidence suggests that oral microorganisms can translocate to the lungs through microaspiration or hematogenous spread, potentially disrupting pulmonary microbial homeostasis and contributing to lung carcinogenesis (Fig. 1). This process may be mediated through chronic inflammation triggered by periodontal pathogens such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum [12].

Fig. 1.

Oral flora and lung cancer. Oral flora can promote the occurrence of lung cancer through inflammatory response, immunosuppression, and metabolites. Therapeutic strategies targeting pathogenic oral flora-such as antimicrobial peptides, probiotic supplementation, and dietary interventions-show potential to attenuate cancer progression

There was a gradual increase in microbial load from surrounding normal lung tissue to lymphocytes to lung cancer cells to the upper respiratory tract, suggesting that bacteria in lung tumors may originate from the oral cavity [1]. Recent studies employing spatial meta-transcriptomics have revealed significant microbial load gradients in lung tissue, with tumor cells showing higher bacterial burdens compared to surrounding immune and stromal cells [1]. Notably, microbial profiling demonstrates reduced α- and β-diversity in non-small cell lung cancer (NSCLC) tumors relative to adjacent normal tissue [2], along with tumor-specific depletion of commensal genera (Fusobacterium, Streptococcus) and enrichment of potential pathogens (Aeromonas, Sphingomonas) [3]. Clinical investigations have identified distinct oral microbial signatures associated with lung cancer risk, including increased abundance of CW040 order bacteria and reduced overall microbial diversity in affected individuals [4].

Stage-specific microbial alterations have been observed, with advanced disease showing increased phylogenetic diversity and enrichment of particular taxa such as Thermi and Legionella in metastatic cases. In addition, among the predicted KEGG modules and pathways, the relative abundance of the flora in the excretory system module, amino acid metabolism, and aldosterone regulation of sodium reabsorption was increased in the flora of patients with stage IV compared with patients with stages IA to IIIA [25]. In contrast, in stage IIIB and IV patients, the flora had decreased abundance in signal transduction.

Current research primarily focuses on the overall association between oral microbiota and lung cancer risk, while its correlation with specific histological subtypes remains unclear. Notably, existing data demonstrate that adenocarcinoma exhibits significantly higher microbial phylogenetic diversity compared to squamous cell carcinoma [26]. At the genus level, the abundance difference between lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) was 13. LUSC shows 63 differentially abundant genera compared to benign tissue, while LUAD shows 4 differentially abundant genera [27]. Potential diagnostic biomarkers emerging from these studies include elevated Capnocytophaga and Veillonella in LUSC [28], Bacillus and Castellaniella in LUAD [29], and characteristic Streptococcus patterns in NSCLC saliva samples [30]. These differences suggest that distinct lung cancer subtypes may harbor unique microbiome signatures. However, the direct relationship between oral microbiota and specific histological types of lung cancer requires further validation through large-scale, multicenter studies.

Environmental factors

Smoking remains the leading cause of lung cancer, with emerging evidence suggesting its carcinogenic effects may be mediated through alterations to both oral and lung microbiomes. Studies demonstrate that smoking significantly alters oral microbial composition, promoting early colonization of pathogens and exacerbating oxidative stress in the oral cavity. These changes create a pro-inflammatory environment where cytokine levels correlate with commensal bacteria specifically in smokers [30]. Importantly, smoking cessation appears to restore a healthier oral microbiome, with former smokers showing microbial profiles similar to never-smokers [31].

Microbiome analyses reveal distinct smoking-associated patterns: bronchoalveolar lavage samples from smokers with lung cancer show increased Firmicutes and Porphyromonas spp. Along with decreased Haemophilus spp. [32], while salivary samples from healthy smokers demonstrate elevated Prevotella and Megasphaera with reduced Capnocytophaga and Neisseria [33]. Mouse models further show that smoke exposure decreases beneficial taxa like Oceanospirillales and Lactobacillaceae while increasing pro-inflammatory markers [34]. Notably, the Aspergillus genus appears particularly abundant in malignant lung tissues, suggesting a potential role in carcinogenesis [35]. Nejman et al. from smokers' tumors Smoke-related metabolite degradation pathways were identified in lung bacteria obtained from smokers' tumors [36]. These microorganisms may promote lung carcinogenesis by stimulating lung cell proliferation and suppressing immune responses. In addition, oxidative stress in the oral cavity may also negatively affect the lungs and increase the risk of lung cancer.

Airborne pollutants, such as soot and chemicals, can directly alter the balance of the microbiome in the lungs. These contaminants may promote the growth of certain pathogens and inhibit the activity of other microorganisms [37]. Different climatic and geographical environments affect the type and number of microorganisms in the air, and these factors also indirectly affect the composition of the lung microbiome.

These findings offer novel insights into the mechanistic links between environmental exposures and lung carcinogenesis through microbiome modulation. However, several critical knowledge gaps remain that warrant further investigation. First, the precise mechanisms by which environmental factors alter oral and pulmonary microbial ecosystems require elucidation, particularly given the technical challenges associated with low-biomass lung microbiome sampling. Second, the observed associations between specific microbial signatures and lung cancer risk need validation in larger, prospective cohort studies to establish causal relationships. Third, comprehensive characterization of the metabolic pathways activated by environmental toxicants in microbial communities may reveal new biomarkers for early detection or therapeutic targets. Addressing these research priorities will advance our understanding of the environment-microbiome-lung cancer axis and its clinical applications.

Common cancer-causing oral microorganisms

Periodontal pathogens-P. gingival and F. nucleatum

Porphyromonas gingivalis (P. gingivalis) is the dominant bacterium in the oral cavity and a common oral pathogen [38]. Porphyromonas gingivalis is involved in the development and progression of several tumors, including lung cancer [39–41]. Porphyromonas gingivalis in the oral cavity is significantly more abundant in cancerous tissues of small-cell and non-small-cell lung cancers compared to adjacent lung tissues, and its infection is strongly associated with smoking, alcohol consumption, lymph node metastasis, and clinical staging. In addition, lung cancer patients with Porphyromonas gingivalis infection had significantly lower survival rates and median survival times [41]. The oral microecological imbalance may cause P. gingivalis to colonize the lungs, causing the release of inflammatory factors and exerting immunosuppressive effects [42, 43], and also affecting the function of P53 [44], thus promoting the proliferation and metastasis of cancer cells. Zhou et al. found that Porphyromonas gingivalis counts showed a significant positive correlation with antibody ratios, and that serum IgG antibody levels against P. gingivalis were positively related to the occurrence of lung cancer [45]. Additionally, Fusobacterium nucleatum (F. nucleatum) levels appear linked to immunotherapy resistance, with higher abundance associated with poor response to PD-1 blockade.

The correlation between antibody levels to periodontal pathogens (e.g., P. gingivalis and F. nucleatum) and the development of lung cancer provides useful clues for exploring new therapeutic options for lung cancer. However, further research is needed to quantify this relationship and elucidate the underlying molecular mechanisms. Understanding how P. gingivalis influences immune modulation and inflammatory pathways could open new avenues for prevention and therapeutic strategies targeting the oral microbiome in lung cancer management.

Veillonella and Prevotella

The healthy oral microbiome is characterized by dominant genera such as Streptococcus, Prevotella, Fusobacterium, Actinomyces, Neisseria, Gemella, and Veillonella [46]. Notably, Veillonella and Prevotella, while abundant in healthy individuals, are frequently associated with lung cancer [47, 48]. Genomic studies reveal the enrichment of these genera, along with Haemophilus, Clostridium, and Gemella, in patients with advanced-stage (IIIB-IV) lung cancer. Specific operational taxonomic units (OTUs) of Veillonella, Prevotella, and Streptococcus correlate with poorer prognosis, with Veillonella exhibiting the highest relative abundance in late-stage disease [30].

Veillonella is linked to key oncogenic pathways, including IL-17 signaling, chemokine-mediated inflammation, and PI3K-Akt and JAK-STAT activation. Clinically, its abundance in non-small cell lung cancer (NSCLC) saliva positively correlates with neutrophil–lymphocyte ratio, while Streptococcus shows an inverse relationship with lymphocyte-monocyte ratio [30]. Beyond direct host interactions, Veillonella modulates microbial communities, promoting Pseudomonas aeruginosa colonization in tumor environments—a phenomenon associated with elevated TNF-α and worsened outcomes [49]. This may explain the frequent enrichment of P. aeruginosa in lung cancer patients.

Similarly, Prevotella is consistently enriched in lung cancer [50] and activates ERK and PI3K signaling pathways [46, 51, 52]. These findings suggest potential synergistic roles for Veillonella and Prevotella in lung cancer progression through shared inflammatory and proliferative mechanisms. Further research is needed to elucidate their precise contributions and therapeutic implications.

Streptococcus

Emerging evidence suggests that Streptococcus, while a commensal organism in healthy oral microecology, may transform into a pathogenic entity contributing to lung carcinogenesis under conditions of microbial imbalance. Multiple studies have demonstrated significant enrichment of Streptococcus species at tumor sites compared to adjacent normal tissue in lung cancer patients [53]. This observation is further supported by findings of oral Streptococcus enrichment in the lower respiratory tracts of affected individuals, accompanied by distinct transcriptomic signatures associated with lung cancer pathogenesis [52]. The potential mechanisms may involve induction of chronic inflammation via macrophage activation and subsequent release of pro-inflammatory cytokines (IL-1, TNF-α); modulation of immune responses leading to tumor-promoting microenvironments; activation of critical oncogenic pathways (ERK and PI3K signaling) in airway epithelial cells; contribution to pulmonary dysbiosis that may further exacerbate carcinogenic processes [52, 54]. While the precise causal relationship between Streptococcus infection and lung cancer development requires further elucidation—particularly regarding whether observed effects are direct or mediated through ecological disruption—current evidence strongly supports the potential utility of Streptococcus as a predictive biomarker for lung cancer risk assessment. Future investigations should prioritize molecular-level characterization of streptococcal-host interactions to delineate the exact mechanisms underlying this association.

Sphingomonas

Sphingomonas spp. are also opportunistic pathogens that can be detected from a wide range of water resources as well as the human oral cavity. In a study on the relationship between respiratory flora and clinicopathologic features of lung cancer, the four genera with the highest relative abundance and proportions found by OTU annotation were Haemophilus spp. (9.54%, 0.20%, 13.59%), Streptococcus spp. (4.82%, 0.17%, 0.19%), Sphingomonas spp. (0.03%, 0.10%, 15.70%), and Shortwave Aeromonas spp. (20.29%, 34.32%, 12.04%). Sphingomonas and Bacillus spp. were also relatively more abundant in non-smoking female lung cancer patients, while controls showed higher abundance of Fusobacterium spp. and Streptococcus spp. [27]In addition, microbial RNA and host gene expression RNA sequencing of tissue-paired specimens in LC patients with indoor pollution factors showed that Sphingomonas spp. and Chilean Sphingomonas-containing cassette bacteria may be associated with epithelial damage and chronic inflammation [55]. The correlation between Sphingomonas spp. and disease-free survival was confirmed in a study by Peters et al.

Mechanism of lung cancer caused by oral pathogenic bacteria

The potential involvement of oral pathogenic bacteria in cancer development represents an emerging field of significant scientific interest. Current evidence suggests these microorganisms may contribute to oncogenesis through multiple interconnected mechanisms following successful colonization. The oral microbiome influences distal pathology through both direct bacterial actions and indirect community-mediated effects. Primary mechanisms include: (1) induction of chronic mucosal inflammation leading to cumulative DNA damage and mutagenesis, (2) production of carcinogenic metabolites and toxins that disrupt normal cellular functions, and (3) modulation of host immune responses that compromise tumor surveillance capabilities. These pathways collectively create a microenvironment conducive to malignant transformation and progression. Elucidating these oral microbiome-cancer relationships holds substantial translational potential, offering novel avenues for preventive strategies, diagnostic biomarkers, and therapeutic interventions in clinical oncology practice.

Inflammation response

Chronic inflammation represents both a cause and a consequence of tumor development, with oral mucosal diseases serving as a paradigm for this relationship. Alterations in the oral microenvironment disrupt microbial homeostasis, enabling pathogenic bacteria within biofilms to produce harmful metabolites that compromise epithelial integrity. While acute inflammatory responses facilitate pathogen clearance, persistent inflammation induces detrimental effects, including the reprogramming of epithelial cells into cancer stem cells (CSCs) through transcription factors such as NF-κB and STAT3. These CSCs contribute significantly to tumor initiation, progression, and therapeutic resistance by increasing the aggressive subpopulation within tumors [56].

Experimental evidence demonstrates that airway epithelial cells exposed to Streptococcus, Prevotella, and Mycobacterium exhibit upregulated ERK and PI3K signaling pathways, promoting cellular transformation [57, 58]. While commensals like Streptococcus salivarius maintain immune homeostasis, pathogenic species such as Fusobacterium nucleatum trigger aberrant inflammatory responses [19, 58]. It has been shown that F. nucleatum infection may lead to abnormal immune-inflammatory responses in intestinal epithelial cells and that F. nucleatum has a significant aggregation in the inflammatory bowel tissues of patients with inflammatory bowel disease. It can be hypothesized that F. nucleatum may also cause damage to respiratory epithelial cells and disrupt the integrity of the epithelial barrier through the promotion of the release of inflammatory factors such as IL-β and TNF-α, creating an opportunity for more bacteria to invade the respiratory epithelium, ultimately leading to lung tumorigenesis. Furthermore, lung-associated bacteria stimulate myeloid cells to produce IL-1β and IL-23 via MyD88-dependent pathways, activating γδ T cells and IL-17 production, which collectively promote tumor-proliferative inflammation [59, 60].

Additional studies reveal that Porphyromonas gingivalis exacerbates tumor invasiveness through multiple mechanisms: (1) upregulation of matrix metalloproteinases (MMP-1, MMP-9, MMP-10), leading to extracellular matrix degradation [61]; (2) FimA-mediated epithelial-mesenchymal transition [62, 63]; and (3) dysregulation of cell cycle progression via p53 and PI3K pathways. Systemic exposure to P. gingivalis or its lipopolysaccharide (LPS) elevates pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) [64, 65], further reinforcing a tumor-permissive microenvironment. These findings underscore the multifaceted role of oral pathogens in driving carcinogenesis through both localized and systemic inflammatory cascades, highlighting their potential as therapeutic targets in cancer prevention and treatment.

Immuno-avoidance and immunosuppression

Emerging research in mucosal immunology highlights the critical role of microbial communities in maintaining epithelial barrier integrity and immune homeostasis. The commensal microbiota actively shapes dendritic cell (DC) development and function, enabling rapid host defense through coordinated cytokine, chemokine, and T-cell responses. This microbial-immune crosstalk is mediated through type I interferon (IFN-I) signaling, which sustains DC antimicrobial capacity while preserving immune tolerance [66]. Comparative studies in germ-free versus conventional mice demonstrate profound immunological differences: germ-free animals exhibit significantly reduced IL-1, IL-23, IL-17, and ROR-γt expression in γδ T cells within secondary lymphoid organs. Conversely, antibiotic-mediated microbiota depletion in tumor-bearing models reduces pulmonary regulatory T cells (Tregs), enhances effector cell activity, and suppresses metastasis—effects correlated with decreased pulmonary colonization by Streptococcus, Aspergillus, and Actinobacillus species [63, 67]. Innate lymphoid cells (ILCs) have been well-established as crucial regulators that maintain immunological homeostasis by exerting dual functions in both innate and adaptive immunity. Based on distinct developmental pathways, characteristic transcription factor expression profiles, and effector functions, ILCs are primarily categorized into three subsets: ILC1, ILC2, and ILC3 [68]. These immune cells play pivotal roles in host defense by orchestrating acute inflammatory responses against infections, while simultaneously promoting inflammation resolution and tissue repair in barrier organs, particularly the lungs and intestines [69]. Among them, the ILC2 subset in lung tissue is particularly critical, and its characteristic secretion of type 2 cytokines such as IL-5 and IL-13 is not only directly involved in the innate immune response but also activates the Th2 adaptive immune response, linking the innate and adaptive responses [70].

At the oral mucosal interface, pathogenic overgrowth of Streptococcus sanguinis-related microorganisms can initiate localized immunopathology through Langerhans cell activation and cross-reactive autoimmunity targeting epithelial heat shock protein homologs. This process drives cytotoxic T lymphocyte (CTL)-mediated epithelial damage characteristic of recurrent aphthous ulceration [71]. Fusobacterium nucleatum induces metabolic reprogramming in cancer cells through the GalNAc-autophagy-TBC1D5-GLUT1 signaling axis: By degrading TBC1D5, it promotes GLUT1 membrane localization, enhancing glucose uptake, and accelerating glycolysis, leading to substantial lactate accumulation. The accumulated lactate further drives the polarization of tumor-associated macrophages (TAMs) toward the M2 phenotype [72]. These M2 macrophages secrete immunosuppressive factors (e.g., IL-10, TGF-β) and pro-angiogenic factors (e.g., VEGF), fostering an immunosuppressive tumor microenvironment (TME) that facilitates tumor growth, angiogenesis, and metastasis [73]. Through TIGIT receptor engagement, F. nucleatum further impairs tumor-infiltrating lymphocyte and natural killer cell cytotoxicity [74]. Moreover, persistent lactate accumulation not only sustains a pro-tumor acidic microenvironment but also establishes a positive feedback loop by continuously recruiting and reprogramming TAMs, thereby exacerbating immune evasion [72].

The functional interplay between Treg and Th17 cells, initially characterized in oral Candida infections, demonstrates critical importance in pulmonary immunity [75]. Th17 cells exhibit context-dependent effects in lung tissues through their signature cytokines IL-17 and IL-22. IL-17 enhances host defense by stimulating bronchial epithelial cells to produce neutrophil chemoattractants, antimicrobial peptides, and increased bicarbonate/chloride secretion—collectively strengthening the airway's antimicrobial barrier. Conversely, IL-22 promotes tissue protection by inducing goblet cell mucus production and epithelial proliferation [76]. However, when dysregulated, these same Th17-mediated mechanisms can drive pathological inflammation in the lung [77, 78]. This functional duality underscores the delicate balance between protective immunity and inflammatory damage in respiratory tissues, with important implications for understanding chronic pulmonary diseases. The pleiotropic nature of Th17 responses highlights their potential as therapeutic targets in lung inflammation while emphasizing the need for precisely modulated interventions.

Carcinogens and metabolites

Mounting evidence demonstrates that metabolites derived from oral microbiota significantly contribute to carcinogenesis through multiple interconnected pathways, including the promotion of cellular mutagenesis, modulation of inflammatory responses, and alteration of immune surveillance. These microbial metabolites can be systematically classified into four major categories based on their biochemical origins and functional properties, each exhibiting distinct roles in both physiological homeostasis and pathological processes [79] (Fig. 2).

Fig. 2.

Microbial metabolites promote lung carcinogenesis through multiple pathways. a. Short-chain fatty acids (butyrate/succinate) recruit myeloid-derived suppressor cells (MDSCs) to suppress anti-tumor immunity; b. Amino acid metabolites potentiate pathogenicity, activate AHR-dependent immunity, and induce Foxp3 + Treg immunosuppression; c. TMAO disrupts reverse cholesterol transport and promotes foam cell formation; d. Secondary metabolites stimulate the secretion of pro-inflammatory molecules and induce M1-type macrophage polarization

Primary metabolites, predominantly short-chain fatty acids (SCFAs), represent crucial mediators of microbial influence on host physiology. Derived from microbial fermentation of carbohydrates and amino acids, SCFAs exert concentration-dependent effects ranging from milligram-level cytotoxicity—inducing apoptosis, autophagy, and pyroptosis—to microenvironmental modulation through pH reduction [80]. This acidification creates a selective growth advantage for acid-tolerant bacterial species while simultaneously enhancing tumor cell metastatic potential. Furthermore, SCFAs orchestrate immunosuppressive niche formation through the recruitment and expansion of myeloid-derived suppressor cells (MDSCs) [81]. Specific SCFA species demonstrate unique biological activities: sodium butyrate downregulates intercellular adhesion molecule-1 (ICAM-1) expression, impairing immune cell trafficking and effector functions [82], while succinate drives oncogenic transformation through epigenetic reprogramming (global 5-hydroxymethylcytosine reduction), stabilization of HIF1α, metabolic shift toward aerobic glycolysis, and promotion of epithelial-mesenchymal transition (EMT) and cancer stemness [24, 83].

Amino acid metabolism constitutes a predominant metabolic pathway in oral microbial communities, generating diverse bioactive compounds with significant pathophysiological implications. The metabolic cascade begins with proteolytic degradation to peptides and amino acids, followed by microbial conversion into four major classes of derivatives: (1) Acidic amino acid metabolites (aspartate-derived butyrate and propionate) that amplify inflammatory responses [79]; (2) Basic amino acid products (ornithine-derived polyamines) that enhance respiratory pathogen virulence [84]; (3) Aromatic amino acid derivatives (tryptophan catabolites including indole and phenolic compounds) that modulate immune responses through aryl hydrocarbon receptor (AHR) activation [79]; and (4) Sulfur-containing amino acid metabolites (hydrogen sulfide) that exhibit paradoxical effects—inducing pro-inflammatory cytokine release (IL-1β, IL-18) while simultaneously promoting Treg-mediated immunosuppression via Foxp3 modulation [85, 86]. Notably, lysine-derived cadaverine demonstrates potent antitumor activity through multiple mechanisms: reversal of endothelial-mesenchymal transition, inhibition of cellular motility and invasion, suppression of mitochondrial oxidative metabolism, and induction of oxidative stress via disruption of the NRF2/KEAP1/GPX3 antioxidant axis coupled with upregulation of inducible nitric oxide synthase (iNOS) [87].

Lipid metabolites, particularly trimethylamine N-oxide (TMAO) derived from hepatic oxidation of microbial trimethylamine (TMA), have emerged as significant risk factors in carcinogenesis. Elevated TMAO levels demonstrate a specific association with colorectal cancer risk in vitamin B12-deficient postmenopausal populations, mediated through disruption of reverse cholesterol transport pathways and promotion of foam cell formation [88].

Secondary metabolites, represented by ribosomally synthesized and post-translationally modified peptides (RiPPs), exhibit remarkable functional duality—capable of inducing both pro-inflammatory responses and microbial dysbiosis while simultaneously demonstrating antimicrobial and anticancer properties [79].

This comprehensive metabolic network underscores the complex interplay between oral microbiota and host physiology in cancer development, highlighting the need for continued investigation into their precise mechanistic roles and potential translational applications in cancer diagnostics and therapeutics. The multifaceted nature of these microbial metabolites suggests they may serve as both biomarkers of disease risk and potential targets for therapeutic intervention.

Rely on the microbiome to optimize the diagnosis and treatment strategy of lung cancer

Antimicrobial peptides

Antimicrobial peptides (AMPs) constitute a diverse group of small, naturally occurring peptide molecules that serve as crucial components of the innate immune system. These evolutionarily conserved compounds demonstrate broad-spectrum biological activities, including potent antimicrobial, antiviral, antifungal, and antitumor properties. In the oral cavity, AMPs function synergistically with other antimicrobial factors to form an intricate defense network that maintains microbial homeostasis while protecting against pathogenic invasion. Their mechanism of action is fundamentally linked to their unique structural characteristics, enabling them to disrupt bacterial membrane integrity through interference with ion channels and membrane proteins, ultimately leading to cytoplasmic leakage and cell death [89].

The oral cavity produces a remarkable array of antimicrobial peptides (AMPs) that serve critical roles in maintaining microbial homeostasis and host defense. Among these, β-defensins demonstrate broad-spectrum activity against key periodontal pathogens including Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, and Streptococcus pyogenes, as well as fungal species such as Candida albicans and non-albicans Candida. Beyond their direct microbicidal effects mediated through membrane disruption, β-defensins contribute to immune regulation by facilitating chemotaxis of T cells and dendritic cells, thereby bridging innate and adaptive immunity [90]. LL-37, another prominent oral AMP, exhibits unique mechanisms of antimicrobial action through biofilm disruption and direct binding to bacterial cell walls, effectively inhibiting microbial adhesion. This peptide additionally demonstrates significant immunomodulatory capacity, showing a strong affinity for various peripheral blood immune cells and enhancing their functional activation [91]. Histatins represent a particularly effective antifungal defense component, employing dual mechanisms of biofilm interference and mitochondrial respiration inhibition to induce metabolic collapse and cell death in Candida species [92, 93].

Clinical investigations using 16SrDNA sequencing analysis have revealed that therapeutic applications of AMPs can significantly modulate oral microbiota composition. Zhao et al. demonstrated that antimicrobial peptide-containing chewing gum administration in healthy volunteers resulted in increased abundance of beneficial taxa (Ciliophora, Leptotrichia, and Actinobacteria) concurrent with reduction of potentially pathogenic genera (Neisseria and Haemophilus) [94]. Remarkably, several AMPs show promising antineoplastic properties with specific activity against non-small cell lung cancer (NSCLC): streptococcin ZP, produced by Lactococcus lactis, induces mitochondrial-mediated apoptosis and G0/G1 cell cycle arrest through ROS generation pathways, while also inhibiting cancer cell migration and clonal expansion [95]; buforin IIb, a synthetic derivative of buforin II, demonstrates enhanced cytotoxicity against multiple NSCLC cell lines and xenograft models via mitochondria-dependent apoptotic pathways [96]; bombinin H2 and temporin A exhibit selective tumoricidal activity against NSCLC cell lines [97].

These findings highlight the therapeutic potential of AMPs in oncology, particularly for aggressive, metastatic NSCLC. The multifaceted mechanisms of action—combining direct tumoricidal effects with immunomodulatory properties and microbiota regulation—position these molecules as promising candidates for development as adjuvant anticancer therapies. Future development may focus on structural optimization to enhance potency and stability, combinatorial approaches with existing therapies, and the development of innovative delivery systems. As research continues to elucidate their precise mechanisms of action and technological advances facilitate their clinical application, these multifunctional peptides are poised to emerge as valuable adjuvants in oncology, potentially improving treatment outcomes and patient survival rates through their unique combination of antimicrobial and antitumor properties.

Probiotic bacteria

Probiotics—live microorganisms that confer health benefits when administered in adequate amounts—are widely used in food and supplements, though their broader mechanisms remain incompletely understood. In oral and respiratory contexts, probiotics competitively inhibit pathogenic bacteria by colonizing host surfaces, producing antimicrobial metabolites, and disrupting biofilm formation. Lactobacillus casei (AgNPs-LC) demonstrates broad-spectrum antibacterial effects against Gram-positive and Gram-negative pathogens, including Pseudomonas aeruginosa, by suppressing biofilm formation and virulence factor production [98]. Notably, AgNPs-LC exhibits anticancer properties, inhibiting migration and invasion in A-549 lung cancer cells while enhancing macrophage and natural killer cell activity [99].

Other probiotic strains, such as Pediococcus pentosaceus FP3 and Lactobacillus salivarius FP25/FP35, induce apoptosis and suppress proliferation in colon cancer cells (Caco-2) [100]. Lactobacillus rhamnosus GG (LGG), the most extensively studied probiotic in oncology, exerts anti-inflammatory effects by downregulating CXCL-2, IL-6, and IL-8 [101, 102]. In murine models, LGG mitigates chemotherapy-induced intestinal damage, preserves epithelial barrier integrity, and maintains microbial balance [103].

Despite these benefits, key challenges persist: the mechanisms underlying probiotic-mediated anticancer effects require deeper investigation, and overuse risks dysbiosis. Further research should optimize strain-specific applications, dosing, and safety to harness probiotics for cancer prevention and therapy effectively. Their dual role in modulating microbiomes and immune responses positions probiotics as promising adjuncts in managing oral and respiratory diseases.

Food therapy

Nutritional intake exerts a significant influence on the composition and function of oral microbial communities, establishing a potential link between dietary habits and lung cancer risk through microbiome-mediated pathways. A growing body of evidence suggests that specific dietary components can modulate oral ecology in ways that may confer protection against pulmonary carcinogenesis. Probiotic-rich foods, including fermented dairy products and traditional preparations, promote microbial equilibrium through competitive exclusion of pathogenic species and enhancement of beneficial bacterial populations [104]. Concurrently, antioxidant-abundant fruits and vegetables demonstrate protective associations, with meta-analytic data indicating that high citrus consumption correlates with a 9% reduction in lung cancer incidence [105]. Particularly noteworthy are lingonberries, which contain unique polyphenolic compounds demonstrating triple antimicrobial, antioxidant, and anti-inflammatory activity in both experimental and clinical settings [106].

Dietary fiber emerges as another critical component, functioning through multiple mechanisms to support oral and systemic health. By serving as a substrate for beneficial microbial fermentation, fiber enhances α-diversity within oral microbial communities while simultaneously maintaining ecological balance. This microbial modulation translates to reduced systemic inflammation through intricate gut-oral axis signaling pathways [107]. The anti-inflammatory effects appear particularly relevant for lung cancer prevention, given the established role of chronic inflammation in pulmonary carcinogenesis.

Polyphenolic compounds represent perhaps the most pharmacologically active dietary constituents influencing oral microbiota. These plant-derived secondary metabolites exhibit: (1) direct antimicrobial activity against periodontal pathogens including Fusobacterium nucleatum and Porphyromonas gingivalis [108], (2) potent anti-inflammatory effects mediated through NF-κB pathway inhibition and IL-10 upregulation [109], and (3) prebiotic-like stimulation of health-associated Lactobacillus species [110]. Rich sources include red wine [108] (with non-alcoholic components retaining significant bioactivity), green tea [109] (particularly abundant in epigallocatechin gallate), and various berries. Epidemiological investigations consistently demonstrate inverse associations between regular tea consumption and lung cancer incidence [111, 112], suggesting that habitual intake of these polyphenol-rich beverages may disrupt inflammatory cascades relevant to pulmonary malignancy development.

Current evidence supports several evidence-based dietary recommendations for oral microbiome optimization and potential lung cancer risk reduction:

1. Regular consumption of diverse, plant-dominant dietary patterns

2. Incorporation of traditionally fermented foods containing viable probiotic strains

3. Moderate intake of polyphenol-rich beverages including tea and red wine

4. Adequate daily fiber intake from whole food sources

5. Emphasis on antioxidant-rich fruits and vegetables

These nutritional strategies collectively promote oral microbial homeostasis, suppress pathogenic overgrowth, and mitigate systemic inflammation—potentially interrupting critical pathways linking oral dysbiosis to distal carcinogenesis. While observational data remain compelling, further intervention studies are needed to establish causal relationships and quantify the magnitude of lung cancer risk reduction achievable through targeted dietary modifications. Particular emphasis should be placed on elucidating the dose–response relationships for specific bioactive compounds and developing personalized nutrition approaches based on individual microbiome profiles. The accumulating evidence positions dietary modulation as a promising component of comprehensive lung cancer prevention strategies, with oral microbiota serving as both mediator and biomarker of intervention efficacy.

Oral health care

A substantial body of research has established the significant benefits of professional oral healthcare interventions, particularly for populations vulnerable to respiratory infections including elderly individuals and comatose patients [113]. Comprehensive care encompassing teeth, tongue, and denture hygiene, when administered by dental professionals, demonstrates measurable protective effects against pulmonary complications. Systematic evaluations, including the landmark analysis by Khadka et al., have consistently shown that professional oral hygiene interventions substantially reduce the risk of aspiration pneumonia through multiple mechanisms [114].

In healthy individuals, routine activities including mastication, hydration, and standard oral hygiene practices (brushing, rinsing) maintain microbial homeostasis by mechanically reducing pathogenic bacterial loads. However, during periods of compromised host defense—particularly among fasting patients or those with restricted oral intake—the oral microbiome undergoes dramatic shifts characterized by the overgrowth of opportunistic pathogens. This dysbiotic state creates a substantial risk for respiratory pathogen colonization and subsequent pulmonary infection. Clinical evidence demonstrates that targeted oral care protocols, including systematic tooth brushing, can effectively control pulmonary pathogens (Staphylococcus spp., Enterobacteriaceae, Candida spp.) in resting saliva, thereby reducing pneumonia risk in vulnerable populations [115].

The preventive value of oral hygiene extends to surgical settings, where numerous studies have established a clear association between preoperative oral hygiene interventions (professional plaque control, antimicrobial rinses) and reduced postoperative pneumonia incidence [115]. These findings underscore the critical importance of integrating dental professionals into perioperative care teams. Epidemiological investigations reveal striking correlations between poor oral health status and chronic respiratory conditions. Patients with chronic obstructive pulmonary disease (COPD) consistently demonstrate worse oral health parameters compared to controls [116]. These observations highlight the need for enhanced public health initiatives promoting both proper self-care practices and regular professional dental visits as potential strategies for respiratory disease prevention.

The field of oral microbiome research continues to evolve rapidly, with several promising directions emerging: (1) Development of personalized oral care regimens tailored to individual microbial profiles, (2) Advanced interventions targeting specific pathogen-resident community interactions, (3) Integration of oral microbiome monitoring into systemic disease prevention programs, (4) Exploration of novel antimicrobial approaches while preserving commensal communities. These scientific advances promise to revolutionize our understanding of the oral-systemic health connection, potentially yielding new paradigms for preventing and managing respiratory diseases through targeted oral microbiome modulation. The growing evidence base strongly supports the incorporation of professional oral healthcare as a fundamental component of comprehensive medical care, particularly for high-risk populations. Future research should focus on optimizing intervention protocols, establishing cost-effectiveness analyses, and developing standardized guidelines for interdisciplinary patient management.

Microbiotype markers for early lung cancer detection

Liquid biopsy technologies have revolutionized early cancer detection, with circulating microbial DNA (cmDNA) emerging as a promising novel biomarker class that complements existing circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) [117]. Current research has identified 11 microorganisms classified as definitive carcinogens, while tumor microenvironments harbor distinct microbial communities primarily localized within malignant cells and tumor-associated immune cells [118]. The biological sources of cmDNA in cancer patients are multifaceted, originating from: (1) passive release during apoptotic and necrotic processes of tumor-associated microbes, (2) active secretion by viable tumor tissue, and (3) translocation from intestinal microbiota through compromised gut barriers [119]. cmDNA possesses unique molecular characteristics that enhance its diagnostic potential, including tissue-specific microbial signatures and remarkable stability in circulation. Accumulating clinical evidence demonstrates the utility of cmDNA analysis for early detection across various malignancies, including breast cancer, lung cancer, colorectal cancer, and melanoma [120, 121].

These advancements underscore the clinical viability of incorporating microbial biomarkers into multimodal liquid biopsy platforms. Future research directions should focus on standardizing cmDNA detection methodologies, validating microbial signatures across diverse populations, and establishing robust clinical decision thresholds. The integration of cmDNA analysis into existing cancer screening protocols represents a significant opportunity to improve early detection rates while providing novel insights into the role of microbiota in oncogenesis. Further studies are needed to fully elucidate the biological mechanisms governing cmDNA release and to optimize its combined use with other circulating biomarkers for precision oncology applications in clinical practice.

Conclusions and future directions

The oral microbiome plays a crucial role in systemic health, with emerging evidence highlighting its significant impact on lung cancer development. Research indicates that specific pathogenic microorganisms like Porphyromonas gingivalis, as well as commensal bacteria such as Veillonella and Prevotella, may translocate from the oral cavity to the lower respiratory tract, where they promote lung cancer progression by secreting carcinogenic metabolites, activating pro-inflammatory signaling pathways, or inducing a local immunosuppressive microenvironment. Smoking, as a critical environmental factor, not only directly damages the respiratory epithelium but also significantly alters the composition and function of both the oral and pulmonary microbiota, thereby exacerbating pathological changes along the "oral-lung axis" and creating a favorable environment for tumorigenesis.

Current understanding of oral microbial homeostasis regulation and its impact on pulmonary health remains limited, despite growing recognition of the oral-lung axis in disease pathogenesis. While antimicrobial peptides and probiotics have emerged as promising therapeutic candidates, their precise mechanisms of action require further elucidation through rigorous preclinical and clinical investigations. Dietary interventions, particularly increased consumption of plant-based foods rich in polyphenols, demonstrate significant potential in modulating microbial composition by promoting beneficial taxa while suppressing pathogenic bacteria and fungi, thereby attenuating systemic inflammatory responses. Complementary approaches including professional oral care and antimicrobial photodynamic therapy show additional promise in restoring microbial equilibrium. The therapeutic potential of natural compounds, particularly those derived from traditional medicine systems, warrants special attention. Berberine exemplifies this potential through its multimodal anticancer effects, including proliferation inhibition, metastasis suppression, and apoptosis induction, coupled with its ability to modulate gut microbiota. However, the specific applications of phytomedicines in managing oral microbiome-associated respiratory diseases remain underexplored. Current evidence remains preliminary, necessitating systematic studies to evaluate.

Despite established links between oral microbiota and local diseases like periodontitis and oral cancer, research on their role in lung carcinogenesis remains limited, with current hypotheses relying largely on extrapolated mechanisms. Future studies should employ integrated multi-omics approaches to systematically characterize microbial functional profiles, establish more reliable animal models to validate causal relationships, and design rigorous clinical trials to evaluate the predictive value of microbial biomarkers. Furthermore, the development of personalized microbiota-based therapeutic strategies will require deep interdisciplinary collaboration among microbiology, oncology, and clinical medicine. These concerted efforts will ultimately facilitate the translation of basic research findings into clinical applications, providing novel approaches for the prevention and treatment of lung cancer.

Author contributions

Mingzhu Zhou and Yan Liu contributed to the study conception and reviewed the manuscript; Mingzhu Zhou and Xin Yin edited the manuscript; Jiannan Gong and Jianqiang Li supervised the project. All authors contributed to the manuscript revision, read, and approved the submitted version.

Funding

This work was supported by the Shanxi Science and Technology Department Basic Research Program for Young Researchers in the Category of Free Exploration (NO202203021212055), and Shanxi Provincial Scientific Research Funding Program for Returned Overseas Scholars (NO2022-200).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

All authors have made substantial contributions to this study.

Consent for publication

All authors have approved the final version of the manuscript for publication.

Competing interests

The authors declare no competing interests.