1. Introduction

Oral cancer is the sixth most frequent malignant tumor in the human body worldwide, with oral squamous cell carcinoma being the most prevalent kind of oral cancer^[1]. OSCC is an epithelial cancer that can develop in a variety of locations in the oral cavity[2] ^[2]. From 2005 to 2014, Dhanuthai et al[1] ^[1] reviewed the biopsy records of OSCC patients diagnosed in various countries and collected information on lesion sites,they discovered that the most common sites were the tongue , labial or buccal mucosa, gingiva  palate and alveolar mucosa .Among which,  squamous cell carcinoma of tongue is the most common malignancy and accounts for approximately 50% of the cases[3] ^[3] .

Despite the ease with which the oral cavity can be accessed during direct examination, numerous technological advancements in surgical procedures, as well as adjuvant radiation therapy and drug therapy, TSCC patients are frequently diagnosed at later stages due to a lack of early diagnosis based on appropriate molecular markers and new treatments,which has a detrimental effect on survival rates,patients with TSCC had a 50% to 60% 5-year survival rate, but there is any channge in the survival rate over the previous decade[4] ^[4]. In the past, smoking, drinking alcohol, chewing betel nut and  human papillomavirus (HPV) have all been identified as substantial risk factors for OSCC[5] ^[5]. Recent years,with the development of microbial sequencing technology, microbial-host interactions have been shown to have a great impact on human health[6] ^[6]. The oral microbiota , as part of the human microbiomeis ,is crucial for the stability of the a healthy balance between host defense and microbiology,once a disruption of homeostasis and an imbalance in the microbial flora leads to oral diseases and systemic diseases[7] ^[7].  Plenty of studies have backed up the theory that there remain oral microecology disturbances in the incidence and progression of OSCC.According to Yang and Ganly et al.[8 ^[8][9],9], the flora of oral rinse samples between healthy individuals and OSCC patients made a significant difference,for example, at the genus level, Fusobacterium and Prevotella were significantly enriched in oral rinse samples of OSCC patients ; however, the abundance of other genera decreased,such as Streptococcus, Haemophilus,Porphyromonas and Actinobacter.At the same time , the abundance of Fusobacterium has increased  in precancerous lesions and was significantly higher in OSCC4 stage patients , so we  speculated that Fusobacterium is associated with the progression of oral cancer.Besides,it can be seen from the results of Mager、Granato and Guerrero et al. [10-12]^[10][11][12] high abundances of Capnocytophila, Prevotella, Alloprevotella, Prevotella melanogenum and Peptostreptococcus in the saliva  play an important role in the diagnosis of oral squamous cell carcinoma, whereas Veillonella and Rothia are generally more abundant in the saliva of healthy groups.In addition, some results support an increase in the abundance of Fusobacterium and Peptostreptococcus, and the decrease of Firmicutes, Actinobacteria, Streptococcus, and Rothia on the surface of cancer lesions is related to the occurrence and development of OSCC[13,14] ^[13]. Last but not the least, in tumor tissue, ,Fusobacterium, Peptostreptococcus, Campylobacter, Fusobacterium pleomorphic subsp. and Fusobacterium periodontium were also enriched,which exert an essential role in the initiation and development of OSCC[15,16] ^[15][16].

From the above data, we can see that, there is still no clear consensus on the microbiological markers associated with the incidence and progression of OSCC duing to the differences in research methods and study samples. .Besides, current studies mainly focus on the whole oral squamous cell carcinoma, and do not consider the specificity of oral tissues，so little attention has been paid to the relationship between tumors occurring in a single site of the mouth and oral microorganisms,such as tongue cancer with the highest incidence and the worst prognosis. Therefore,this review focus on the disorders of specific microbial associated  with tongue cancer at different niche and taxonomic levels. In addition,by comprehensivly analyzing the interaction mechanism between oral microbiota and malignancies,we also disscussed the potential role of oral microbiota in the management of OSCC. It is hoped that targeting microbiota to optimise cancer therapy outcomes.

2. Specific flora aFlora Associated with tTongue cCancer

The oral cavity is a complex ecological environment, occupied by bacteria, archaea, protozoa, fungi and viruses, among these oral microorganisms, bacteria are the main components[17] ^[17]. According to studies, the bacteria in the human oral cavity are extremely complex, with about 700 species, in which Firmicutes, Actinomyces, Proteobacteria, Fusobacterium, Bacteroidetes and Spirochetes account for 96 percent of the total oral bacteria[18] ^[18]. The oral cavity can provide different habitats for these microorganisms, such as saliva, tooth surfaces, lingual mucosal surfaces, gingival sulcus, buccal mucosal surfaces，owing to these different ecological niches may provide different nutritional conditions for the microorganisms ,so there may be differences in the composition of microorganisms present in these niches[18] ^[18]. Under normal circumstances, these microorganisms maintain a dynamic balance with the host, but when the flora is deviated from the healthy microbiome,which allows pathogenic bacteria to emerge, thrive, and ultimately fostering illness[19] ^[19]. Among oral squamous cell carcinomas, the incidence of tongue squamous cell carcinoma ranks first ^[20]. Not only is it difficult to identify in the early stages, but it also has a high risk of metastasis, postoperative recurrence and mortality rate[21] ^[21]. Sad to say, recent global epidemiological data[22] ^[22] have found that the incidence of tongue squamous cell carcinoma keeps on increasing, primarily in the younger population[23] ^[23]. Therefore, exploring biomarkers associated with tongue cancer could improve clinical outcomes in affected patients. With the development of bioinformatics, more and more studies have proved that the imbalance of specific flora is related to the occurrence of tongue squamous cell carcinoma[24,25] ^[24][25].

2.1. Firmicutes and rRelated bBacteria

The relative abundance of Firmicutes phylum and related bacteria at the genus or species level varies in the parient with TSCC because of the difference of simple disscussed .At the phylum level , Pushalkar et al. [24]^[24] found that the  detection frequency of Firmicutes phylum in tumor tissue (85 percent) higher than non-tumor tissues (74.6 percent). However, Schmidt et al. ^[26] synthesized the 16SrDNA hypervariable area amplicons and observed the opposite result  that when compared to the contralateral anatomical normal location, the Firmicutes phylum were dramatically decreased in the surface of precancerous and cancer lesions of the tongues. In addition, by 16S rDNA sequencing ,Ye et al. [27]^[27] compared the microbes of cancer tissues and adjacent normal tissues of 23 TSCC and found that the abundance of Firmicutes did not differ between the two groups.From the data listed above,in the tissue  and the surface of cancer lesions of the tongues,there is not a consistent results about the channge of Firmicutes phylum .It's worth mentioning that at the genus level, we can draw a conclusion that Streptococcus in the mouthwash 、tissue even surface of cancer lesions of patients with TSCC was all shown to be lower in comparison to controls by comprehensivaly analysing the consequent of  Schmidt ^[26]and Ye et al.[27] ^[27]. At the same time ,other genus from the Firmicutes phylum,such as Micromonas, Clostridium and Peptostreptococcus, have all been found to be enriched in tongue cancer as compared to controls in other investigations[16,28] ^[16][28]. At the species  level, Streptococcus pneumoniae deceeased in the tissue and Streptococcus salivarius increased in the saliva of the patient with TSCC in contrast with  control group[3,27] ^[3][27].

Though the result of Firmicutes and related bacteria in TSCC varies, on the whole, the reduction in the abundance of Streptococcus and Streptococcus pneumoniae and the increase in the  abundance of Micromonas, Clostridium, Peptostreptococcus and Streptococcus salivarius may be linked to the development of tongue cancer.

2.2. Actinobacteria and rRelated bBacteria

A paired analysis ^[29] about  head and neck squamous cell carcinoma tissues and normal tissues found that Actinobacteria decreased in tongue cancer tissues, with the effect being more pronounced in high-stage patients. Similar results have appeared in other studies which compared tumor tissue, normal paracancerous tissue, and salivary flora in 6 tongue cancer, 3 cheek cancer, 11 gum cancer, and 3 mouth floor cancer patients,finally proved that abundance of Actinobacteria was lower in all cancer tissue samples when compared to paracancerous tissue, while the level of the Actinobacteria-related taxa Rothia mucilaginosa was considerably enriched, notably in tongue cancer tissue[30] ^[30]. But there is  a paradoxical result told by Al-Hebshi et al[15] ^[15]. that the abundance of Rothia mucilaginosa was significantly higher in the healthy group than in the case group when comparing cancer tissue samples of 10 people with tongue cancer with  anatomical deep epithelial swab samples matched to lesions in OSCC patients of 20 healthy controls. Another bacteria should be discussed was the situation of Rothia .When Pushalkar et al. ^[31] evaluated the salivary microorganisms of patients with tongue squamous cell carcinoma and healthy controls, they found the amount of Actinobacteria-associated Rothia was higher in patients' saliva.But in  the comparison between canncer tissue  and adjacent normal tissues from thirty-seven oral tongue squamous cell carcinoma, Michikawa et al.[32] ^[32] found Rothia were enriched in adjacent normal tissues.Thus it can be seen Actinobacteria-related bacteria Rothia and Rothia mucilaginosa display varied expression patterns in different oral sample in patients with TSCC at the moment, and additional experiments are needed in future research to demonstrate the association between tongue cancer and Actinobacteria and related bacteria

2.3. Proteobacteria and rRelated bBacteria

Individuals with TSCC had a larger proportion of Neisseria macacae in their saliva, a higher proportion of Neisseria flavescens in tongue cancer tissue and on the tongue cancer surface have been discovered[30] ^[30]. However, researchers who looked at the germs in malignant and non-cancerous tissues from 23 TSCC discovered that Neisseria spp. were less abundant in diseased tissues[25] ^[25]. This might be because the relationship of bacteria with OSCC varied greatly based on the kind of sample examined, and hence should be interpreted differently depending on the type of sample studied. In addition, Pushalkar et al[24] ^[24] found that the Proteobacteria-related bacteria Campylobacter and Catonella were only consist in the tumor tissues of tongue and floor of mouth tumors, as opposed to normal tissues adjacent to the malignancy. Al-Hebshi et al[33] ^[33] also noticed that Campylobacter and Pseudomonas were significantly higher in cancer tissues than in matched normal deep epithelial samples.And  Pseudomonas aeruginosa, is strongly linked to tongue cancer at the species level.According to the consistent research results of Pushalkar[24] ^[24] and Al-Hebshi et al. ^[33], Campylobacter, Catonella, Pseudomonas related bacteria Pseudomonas aeruginosa are closely related to the occurrence of tongue cancer.Their role in tongue squamous cell carcinoma should be further verified in the future.

2.4. Bacteroidetes and rRelated bBacteria

A previous study comparing cancer tissue, mouthwash, and salivary microbes from patients with oral squamous cell carcinoma by 16S rRNA sequencing found that individuals with tongue cancer had a high abundance of Bacteroidetes, with Prevotella significantly enriched at the genus level[34] ^[34]. Similar results have also been demonstrated in other studies[26] ^[26], Bacteroidetes, notably its linked Prevotella at the genus level and Prevotella intermedia, Prevotella melanogenum at the species level, have dramatically higher abundance in cancer and precancerous tissues from the tongue as compared to normal tissues. In addition, Prevotella was also significantly increased in the saliva of patients with tongue cancer[35] ^[35]. In addition,Hashimoto et al.[36]^[36] compared the saliva microorganisms of healthy, leukoplakia and tongue cancer patients, and the results showed that the saliva of leukoplakia and tongue cancer patients' saliva had higher Porphyromonas gingivalis levels than healthy subjects. Animal studies have also shown that chronic infection with Porphyromonas gingivalis and Fusobacterium nucleatum was found to promote growth and severity of mouse tongue tumors[37] ^[37]. From the above results, the quantity of Prevotella in the saliva, mouthwash and cancer tissues of patients with tongue squamous cell carcinoma rose consistently when compared to the normal control group. Based on the facts, we may conclude that Prevotella and Porphyromonas gingivalis may be vital for the formation of tongue cancer.

2.5. Fusobacteria and rRelated bBacteria

Yang et al. ^[38] compared the microbial structure in mouthwashes of 51 healthy and 197 patients with squamous cell carcinoma of different oral location, found that during the progression from healthy controls,OSCC stage 1 to OSCC stage 4 ,the abundance of Fusobacterium and Fusobacterium nucleatum increased significantly.Besides, in the cancer tissue[26,39] ^[26][39] and on the surface of tongue squamous cell carcinoma[40] ^[40], there remained elevated levels of Fusobacterium ,too.When relationship between tongue, buccal,gingival, and floor of the mouth squamous cell carcinoma and oral microbes were studied , Fusobacterium nucleatum subsp. polymorphism was found to be enriched only in tongue squamous cell carcinoma tissue samples[33] ^[33], demonstrating that Fusbacterium nucleatum subsp. polymorphism is only associated with tongue squamous cell carcinoma. Furthermore, Sanket et al. ^[41] found that internal samples from patients with tongue squamous cell carcinoma showed a low survival rate with a high rate of Fusobacterium infection. Therefore, it is speculated that the rational control of Fusobacterium and its related bacteria is not only helpful for the treatment of tongue squamous cell carcinoma, but also improves the prognosis of patients.

2.6. Oral Microbial Communities cChange in the tumor mTumor Microenvironment

The above describes how individual bacteria in the tumor microenvironment,however It is worth mentioning that in the oral cavity, bacteria can aggregate into colonies to form functional biofilms.The synergistic interaction of polymicroorganisms, eubiotic microbiota, can maintain homeostasis with the host[42] ^[42]. But the change in a single microbiota can cause a cascade of effects, leading to disruption of the normal oral biofilm even the phenomenon being replaced by populations of pathogenic bacteria .. For example,Fn could combinate with other microbial cells and form the common functional group to interact with host,following a pathogenic environment that is not conducive to the health of the host,just like that Fn ,Peptostreptococcus and  Campylobacter, always  be co-existent in tumors and creat a tumorigenic environment that cause the exhaustion of healthy bacteria,such as Streptococcus ^[43]. Explanation of various phenomena suggests that the emergence of pathogenic bacterial populations and the decrease of beneficial bacteria may cause the initiation and progression of OSCC,Therefore,identification of functional comminities assoiated with OSCC is more valuable.

3. Influence of oral mOral Microbes on the oOccurrence of oral sOral Squamous cell cCell Carcinoma

Oral microbes can affect tumorigenesis by being functional of mediating chronic inflammatory states, suppressing immune responses, synthesizing carcinogens, attenuating synthesisof anticancer agents, and promoting cancer cell invasion.

3.1. Mediating cChronic iInflammation and iImmunosuppression

Over the years, inflammatory cells and cytokines found in tumors have the potential to promote tumor growth and progression, and indeed inflammatory molecules have been shown to activate relevant growth signals and promote the proliferation of malignant cells ^[44]. According to research, chronic inflammatory state is considered as one of the possible mechanisms by which oral bacteria participate in the occurrence and development of oral cancer. Periodontitis-related pathogens such as anginosus Streptococcus, Peptostreptococcus sp, Fusobacterium nucleatum, and Porphyromonas gingivalis[45] ^[45] mainly induce OSCC by inducing inflammation. Fusobacterium nucleatum and Porphyromonas gingivalis bind to Toll-like-receptor（ TLR)2 and 4 on the host cell membrane through ligands, and then activate NF-κB through intracellular signaling pathways. Activation of NF-κB  can induce oral epithelial cells to produce various pro-inflammatory cytokines and chemokines, including interleukin (IL)-6, interleukin-8, tumor necrosis factor-α (TNF-α), and interleukin-1β; these inflammatory mediators may induce or promote cell proliferation, mutation, oncogene activation and angiogenesis[46] ^[46]. In addition, some bacteria can induce immunosuppression, thereby promoting the development of OSCC, for example infection of Porphyromonas gingivalis and Fusobacterium promoted the expression of programmed death ligand 1 (PD-L1) on oral squamous cell.PD-L1, an immune inhibitory receptor ligand,upregulation of which on cancer cells and combination with  its receptor,namely programmed cell death protein 1 (PD-1) on activated T cells, would lead to cancer cell escape from immune surveillance,which may promote tumor propagation[32] ^[32] In addition, the amount of F. nucleatum in OSCC patients was negatively correlated with markers of B lymphocytes, CD4 helper T lymphocytes, M2 macrophages, and fibroblasts[47] ^[47], indicating that colonization of F. nucleatum could suppress immunity cell expression.

3.2. Synthesis of cCarcinogens and rReduced sSynthesis of aAnticancer mMetabolites

Oral bacteria can cause DNA damage through itself or its metabolites, which in turn interferes with the cell cycle, changes the cell growth rate, leads to uncontrolled cell growth, directly induces cell canceration or indirectly changes the signal transduction pathway ,and promotes tumorigenesis. First such as bacteria in Bacteroides and Firmicutes can ferment excess host proteins into sulfides and nitrosamines, which can cause DNA damage to oncogenes or tumor suppressor genes[48] ^[48]. Secondly, Oral microbial, such as Neisseria , Rothia mucilage and Streptococcus mitis, can produce carcinogenic levels of acetaldehyde in vitro, ^[49] which can promote cancer development through point mutations after DNA damage and repair[49] ^[49]. Thirdly, Pseudomonas aeruginosa may play an important role in the carcinogenesis of oral cancer by converting nitrite in saliva into nitric oxide ,and converted nitric oxide can cause various cancer-related  manifestations apoptosis, such as cell cycle changes, and angiogenesis, cell invasion and metastasis[50] ^[50]. In addition,according to research, after Porphyromonas gingivalis infects tissues, it can change fatty  acid metabolism and promote 4-nitroquinoline-1-oxide-induced oral carcinogenesis[51] ^[51]. Last but not least,campylobacter was shown to increase a campylobacter-derived genotoxin, the cyto-lethal swelling toxin, which was found to induce DNA double-strand breaks and promote tumorigenesis[52] ^[52]. These cancer-associated bacteria, in addition to acting directly through the carcinogens they produce, can also promote tumor development by reducing the production of anticancer metabolites. As demonstrated by Su et al.[53] ^[53], bacterial disturbances in the oral cavity attenuate the production of anticancer metabolites, such as siderophore-like non-ribosomal peptides and monoterpenoid biosynthesis.

3.3. Enhanced cell iCell Invasion

Epithelial mesenchymal transition (EMT) is a cellular process, usually defined as the loss of the epithelial marker E-cadherin and the increase in the expression of the mesenchymal marker vimentin, which is mainly characterized by the loss of epithelial cells intercellular adhesion and polarity, and acquire invasive and metastatic potential[54] ^[54]. It is worth mentioning that EMT can be activated by some bacreria in the progression of cancer,which may be one of the important mechanisms by which bacteria promote cancer local invasion and distant metastasis[43]^[43]. For example, Fn,cancer-related bacteria can drive OSCC cell migration by upregulating EMT gene[55] ^[55]. Besides, Porphyromonas gingivalis can also iuducte EMC through overexpression of mesenchymal marker, β-catenin[56] ^[56]. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that promote tumor invasion and metastasis by degrading the extracellular matrix[57] ^[57]. A recent study by Harranda et al. [58]^[58] found in an oral tumor mouse model that compared with uninfected mice, the expression levels of MMP1 and MMP9 in oral cancer cells of mice infected with Fn were up-regulated and invasive significantly enhanced.Besides, the phyla of Bacteroidetes, Firmicutes, and Proteobacteria. may also contributie to the upregulation of MMP7,  MMP1 and MMP13  ,followed by remodeling of extracellular matrix ,which would lead to invasiveness and metastasis of OSCC[59] ^[59].

From the above data, it can be seen that the change of single microbial composition or the disorder of multiple microbial groups with the same function is closely related to the occurrence of tongue squamous cell carcinoma

4. Microbiome and cCancer tTherapy

In the clinical, oral cancer is usually treated with surgical resection, followed by chemotherapy or radiotherapy plus radiation. However, all of these patterns which have nonnegligible side effects and adverse effects[60] ^[60]. The good news is that oral microbiota not only  participates in the occurrence and development of cancer through various mechanisms, also modulates cancer treatment responses.So another approach to personalised medicine is to use the Bacteriotherapy to optimize cancer therapies.

Probiotics,including Lactobacillus, Bifidobacterium and Actinomycete ,have been shown to be beneficial to human health,what is the most important is that it possess anti-neoplastic effects[61] ^[61], although as for the role of Probiotics in the treatment of OSCC has been little disscussed. Firstly,it can help in maintaining microbiome homeostasis by preserving the viability of beneficial microbiome in the oral thereby preventing the colonization of bacteria that cause cancer[62] ^[62]. Secondly, probiotics can be used to modulate immunotherapy response in the treatment of OSCC. Infection of Porphyromonas gingivalis and Fusobacterium promoted the expression of PD-L1, upregulation of which on cancer cell can bind to PD-1 on T cells, would lead to immunosuppression. Given host–microbiota interactions can effect immune system of hosts,the effectiveness of cancer therapies could be expanded by the ways of modulating the microbiota. Preclinical studies have also  illustrated probiotics was of the utmost importance in immunotherapy efficacy. Just as it was shown via research that oral bifidobacteria alone has the same anti-tumor impact as PD-L1 antibodies by increasing the number of primed T cells and their concentration in tumor sites[56] ^[56]. Additionally, bifidobacterium suppresses PD-1 expression,which triggers the activation of natural killer (NK) cells, which in turn destroys tumors through the mediation of perforin and IFN-γ[63] ^[63]. L. rhamnosus GG (LGG), another probiotics,can stop tumour progression in mice,this mainly because which can  promote IFN-β production ,which finally enhances cross- priming of anticancer CD8+ T cells[64] ^[64]. These studies have proved the feasibility of microbiota to reverse the immunosuppression in the tumor microenvironment. Thirdly,some probiotics have  anti-neoplastic effects by binding, degradation and inhibition of mutagen;.For instance, in the mice ,lactobacillus fermentum-CQPC08 can  exert a  preventive effect on tongue cancer tinduced by 4-Nitroquineline-1-Oxide[65] ^[65]. And Lactobacillus plantarum (L. plantarum) AS1 ,isolated from fermented food ,can also resist  the role of 1,2-dimethyl hydrazine in  colon tumor in male[66] ^[66]. Last but not least,another mechanism of probiotics to improve  curative effect  is  to promote apoptosis of oral cancer cells.As it has been show,Lactobacillus plantarum was found to induce apoptosis of oral cancer cells by the upregulation of PTEN and MAPK signalling[67] ^[67]. Lactobacillus rhamnosus GG can also Increase apoptosis by increasing the expression of caspase-3, 8, 9, p53, p21 and reducing the BCL-2 & COX-2 levels[68] ^[68]. Such evendences all show that probiotics can not only be used to prevent the initiation of oral cancer,but also to improve treatment effectiveness.

Another enemies of bacteria ,bacteriophages, are the specific group of prokaryotic viruses, which can act on the target bacterial cells through the process of  attachment, injection, replication and translation, assembly and lysis ^[69]. Given the increase in individual bacteria during tumor development, we can take advantage of their bactericidal effects, just as what we expect that a phage strain isolated  from human saliva, have been used to lyse Fn in the cancer tissue of mice[70] ^[70]. Secondly, Recent studies have also demonstrated that phage cocktai,a mixture of phages, can prevent and eradicate pathogenic bacterial biofilms,for instance, after 6 hours of treatment, 98.3 1.4% of the dual-species biofilm and 92.2 3.1% of the multi-species biofilm coverage area had been eliminated by the conjugation of polyvalent Podoviridae phages and magnetic colloidal nanoparticle clusters[71] ^[71]. This suggests that bacteriophages can be a substitutable or complementary treatment strategies targeted carcinogenic biofilms. In addition to these possible mechanisms, phage coats the bacteria and makes it more recognizable by Toll-like receptors (TLR), such as TLR3,TLR7,TLR9,which not only contribute to the effective elimination of pathogenic bacteria in vivo,but also induse  the  production of Type I IFN[72] ^[72]. These cytokines may persistently induce inflammatory processes that provide sustained protection against pathogenic bacterial infections but are not harmful to host health ^[72]. Besides,bacteriophages can resist  the inflammatory response induced by bacteria though stoping T – cell from Proliferation and activation[73] ^[73]. The above results show that in addition to playing direct bactericidal effects, phages can also interact with host immune system to promote the phagocytosis of pathogenic bacteria and prevent the emergence of inflammatory environment caused by pathogenic bacteria, which may give us a future treatment strategies for OSCC.

5. Conclusion

In this paper, by extensively discussing the relationship between oral microbiota and tongue cancer, we conclude that the change of individual bacterial components may cause the interaction between the entire oral population, leading to the transformation of normal biofilm to oncogenic biofilm, resulting in the emergence of oncogenic functional bacterial populations, which finally promote the origenesis and progression of cancer. Probiotics and bacteriophages may play a great role in the clinical management of OSCC in response to the alteration of individual bacterial components in the tumor and the emergence of a pro-cancer environment generated by a functional bacterial population.However,duing to the complexibility between the interactions of microbiota and host, our understanding of the role of oral microbes in the development of OSCC in different locations of the mouth is only the tip of the iceberg.And although targeted microbial therapy has been shown to improve the efficacy of cancer treatment, its role in the treatment of TSCC has rarely been discussed.Therefore, identification of unique flora  that increase the risk of TSCC development and  target microbiological therapies for changes in microbiota composition and function in TSCC need further studied in the future in order to reduce the incidence of oral cancer or improve the outcome of patients with TSCC.

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