Yan Tingting
Zhu Xiaoling1- 1Department of Oncology, Affiliated Hospital of Yunnan University, Kunming, China
- 2First Affiliated Hospital of Kunming Medical University, Kunming, China
The intratumoral microbiota, a critical component of the tumor microenvironment (TME), has been demonstrated to significantly impact tumor progression and therapeutic outcomes. Research indicates that intratumoral microbes can affect tumorigenesis, metastasis, and therapeutic response through various mechanisms, such as inducing DNA damage, activating oncogenic signaling pathways, and modulating immune responses. Furthermore, the microbiota exerts dual regulatory effects on the tumor immune microenvironment (TIME), either enhancing anti-tumor immunity or promoting immunosuppression, thereby presenting novel targets for cancer therapy. In this paper, we conduct a review of the origin and composition of the intratumoral microbiota and its dynamic interactions with the TME by synthesizing data from multiple cancer studies. This review elucidates the complex role of the microbiota within the TIME and explores its potential for clinical application.
1 Introduction
TME constitutes a dynamic ecosystem comprising tumor cells, immune cells, and stromal components. Traditionally, it has been assumed that the interior of solid tumors is a sterile environment, with the exception of cancers associated with infections, such as human papillomavirus (HPV)-related cervical cancer and Helicobacter pylori (H. pylori)-associated gastric cancer. Since the initial discovery of bacteria within human tumors in the 19th century, advancements in macrogenomic sequencing and spatial imaging technologies have progressively elucidated the presence and functional roles of intratumoral microbiota. Research indicates that distinct microbial communities exist within various solid tumors, including colorectal cancer, breast cancer, lung cancer, and pancreatic cancer. The composition of these communities is closely associated with tumor type, host immune status, and clinical prognosis (1). These microorganisms colonize tumor cells, the extracellular matrix, or immune cells in low biomass forms, with compositions exhibiting organ specificity and tumor type dependency. Notably, while the abundance and diversity of tumor-associated microbes are significantly lower than in normal tissues, their metabolic activity and spatial distribution may influence tumor progression by locally regulating immune responses Nevertheless, the precise mechanisms by which microbiota influence the TIME and their effects on therapeutic response remain subjects of debate. This paper aims to elucidate the biological characteristics of intratumoral microbiota, their mechanisms of action, and their interactions with TIME, thereby providing a theoretical foundation for the development of innovative therapeutic strategies.
2 Intratumoral microbial sources and composition
The origins of intratumoral microorganisms remain inadequately characterized, but current evidence indicates that their potential sources primarily include three categories (2–4): (1) sources traversing mucosal barriers, where commensal microorganisms infiltrate the TIME following the disruption of these barriers, as observed in colorectal, pancreatic, and other gastrointestinal tract tumors, as well as lung and cervical cancers; (2) sources originating from adjacent normal tissues; and (3) sources involving hematogenous transmission, wherein microorganisms from the oral cavity, intestines, and other potential sites are transported via the bloodstream to the tumor site, subsequently infiltrating the tumor through compromised blood vessels (5). Furthermore, the hypoxic, nutrient-rich, and immunosuppressive characteristics of the TIME create a conducive environment for the survival of specific microorganisms, such as E. coli and H. pylori (6).
Given the potential for multiple origins of microorganisms within tumors, it can be postulated that the microbial composition across various cancer types is heterogeneous. This hypothesis was substantiated by a comprehensive study conducted by Ravid Straussman’s team, which analyzed the tumor microbiomes of seven distinct cancer types: lung, breast, pancreatic, ovarian, brain, bone, and melanoma. Their findings revealed that each cancer type possesses a unique microbiome predominantly consisting of intracellular bacteria located within cancer and immune cells (1). Recent studies have also revealed fungal components within tumor microbiomes. The same research team mapped fungal profiles across 35 cancer types, finding that while fungi are present in all cancer types, their abundance and diversity correlate with specific cancer subtypes. Nevertheless, bacteria still dominate the microbial communities within tumors (Table 1) (7). This shows that the composition of intratumor microbes is highly heterogeneous and correlates with tumor type, stage and anatomical location. This heterogeneity may influence the biological behavior of the tumor and the response to treatment.
Table 1. Microbial diversity within different tumors and their effects on immunity.
3 Dual role in cancer development and progression
Studies have shown that the intratumoral microbiota can influence tumorigenesis, progression and metastasis through multiple mechanisms, while possessing the dual properties of promoting and inhibiting cancer progression (Figure 1) (2, 5, 6, 8, 9).
Figure 1. Dual immunomodulatory effects of intratumoral microbiota. The tumor microbiome comprises bacteria, fungi, and other microorganisms that profoundly influence tumor progression and treatment response through complex interactions with tumor cells and immune cells. Its dual nature manifests in two ways: on one hand, certain microorganisms promote immune suppression and accelerate tumor progression; on the other hand, harnessing or modifying specific microorganisms can effectively activate anti-tumor immunity.
3.1 Promoting tumor progression
Intratumoral microorganisms can significantly impact tumorigenesis and progression through various mechanisms. These mechanisms potentially include: (1) induction of genomic instability. Intratumoral microbiota can directly drive tumorigenesis by inducing DNA mutations, disrupting genomic stability, activating oncogenic signaling pathways (such as Wnt/β-catenin and NF-κB), and inducing epigenetic modifications (5, 6, 8, 10, 11). For instance, pks+E. coli secretes the genotoxin colibactin, causing DNA double-strand breaks and characteristic mutations (such as APOBEC3B-associated mutations), thereby promoting carcinogenesis (3, 6). H. pylori activates carcinogenic pathways (such as Wnt/β-catenin) through abnormal DNA methylation, driving the progression of gastric adenocarcinoma (6). (2) Immune microenvironment remodeling. Microbiota are key regulators of the TME. By activating pathways such as TLR/NF-κB, they promote the release of proinflammatory factors (e.g., IL-6, TNF-α, IL-1β), thereby inducing γδ T cells to secrete IL-17 and IL-22, ultimately establishing a chronic inflammatory environment (2, 6, 10). Additionally, Clostridium difficile can inhibit anti-tumor immunity by activating PD-L1 or recruiting regulatory T cells (Tregs) (3, 6). In pancreatic cancer, the fungal microbiota can promote tumor growth by recruiting TH2 and ILC2 cells and secreting cytokines such as IL-4, IL-5, and IL-13 (12). (3) Metabolic regulation and metastasis. Microbial metabolites can significantly influence tumor progression (13–15). For example, butyric acid influences gene expression and cancer cell differentiation by inhibiting histone deacetylases (HDACs) (3) Microorganisms carried by circulating tumor cells (such as E. coli) can disrupt the vascular barrier and promote the formation of distant metastatic lesions (16). Additionally, Animal model studies confirm that eliminating bacteria within tumors significantly reduces tumor metastasis, suggesting their critical role in the metastatic process (17). These may be related to microbial metabolites.
3.2 Potential for tumor suppression
Although related reports are scarce, certain tumor-associated microorganisms have also been found to possess antitumor potential. First, direct killing or suppression of tumors (18). For instance, Neutrophils can limit the growth of tumor-associated microorganisms, indirectly inhibiting tumor progression (19). Engineered tumor-targeting bacteria can be used to deliver therapeutic molecules such as interferon-β, reshaping the TIME and suppressing tumor growth and metastasis (20). Second, activating antitumor immunity: Certain bacteria can induce IFN-γ production by activating the STING signaling pathway or releasing outer membrane vesicles, thereby activating T cells and NK cells to enhance antitumor immunity (5, 21). Additionally, certain tumor-associated microorganisms exert indirect effects analogous to “gut probiotics,” potentially exerting antibacterial effects through mechanisms such as antigen presentation and immune response polarization. However, their precise mechanisms within tumors require further investigation (5), potentially involving the activation or inhibition of signaling pathways including ROS, β-catenin, TLR, ERK, NF-κB, and STING (22–24).
4 Relationship between intratumoral microorganisms and the tumor immune microenvironment
Intratumor microorganisms not only play a role in tumorigenesis and development, but may also influence the TIME. Studies have shown that these microorganisms interact with immune cells through multiple mechanisms and exert bidirectional regulatory effects on the TIME, which may either enhance the anti-tumor immune response or promote immunosuppression, thus affecting the therapeutic efficacy (Figure 1).
4.1 Role of intratumoral microorganisms on immune cells
4.1.1 T cells
Intratumoral microorganisms can suppress T cell function by inducing T cell exhaustion, metabolic competition, and inflammation in the microenvironment. Research indicates that certain tumor-associated microbes create an immunosuppressive microenvironment by secreting metabolic byproducts or inducing immunosuppressive cytokines (such as IL-10 and TGF-β), thereby inhibiting T cell activation and proliferation (1, 25). Concurrently, they enhance the suppressive capacity of Tregs by depleting key metabolites like arginine, ultimately suppressing antitumor immune responses (26). This metabolic competition not only impairs effector T cell function but may also lead to premature T cell exhaustion (27). Furthermore, tumor-associated bacteria can promote immune evasion by upregulating PD-L1 expression or inducing T cell exhaustion phenotypes (e.g., Tim-3, LAG-3) (28).
Intratumoral microorganisms have been shown to activate T cell-mediated antitumor immune responses through several mechanisms. First, microbial antigens can induce cross-reactive T cell activation through a “molecular mimicry” mechanism. For instance, functional intratumoral bacteria (such as the AUN strain isolated in this study) can promote tumor-specific T cell killing by releasing pathogen-associated molecular patterns (PAMPs), activating dendritic cells (DCs), and enhancing antigen presentation (28). Escherichia coli and Bifidobacterium bifidum can secrete antigens or metabolites (such as SCFAs) to activate CD8+ T cells via dendritic cells, thereby enhancing their cytotoxic function (5, 29). Secondly, intratumoral microorganisms can potentiate the efficacy of immune checkpoint inhibitors by activating the interferon signaling pathway through pattern recognition receptors such as Toll-like receptors (TLRs) and STING, which in turn upregulates PD-L1 expression (5). Finally, intratumoral microorganisms can enhance T-cell infiltration. For example, Fusobacterium nucleatum promotes CD8+ T-cell recruitment in colorectal cancer by modulating chemokines (e.g., CXCL10) and inhibits PD-1 expression on CD8+ TILs and reactivates their effector function (30, 31).
4.1.2 Regulatory T cells
Intratumoral microorganisms may influence the number or function of Tregs by releasing metabolic products. Initially, intratumoral microbes mediate Treg expansion through metabolic products. For instance, SCFAs promote Treg differentiation and function by inhibiting HDACs or activating G protein-coupled receptors (such as GPR43). They also maintain the immunosuppressive phenotype of Tregs by enhancing the epigenetic stability of the Foxp3 gene (32). Lactobacillus metabolizes tryptophan to produce indole-3-propionic acid, which directly induces Treg differentiation and enhances their suppressive activity by activating the AhR (33, 34). Furthermore, Peptidoglycan or LPS released by Gram-positive bacteria activate pattern recognition receptors on Treg surfaces (e.g., TLR2, NOD2), inducing them to secrete IL-10 and TGF-β, thereby enhancing immunosuppressive functions (35, 36). These studies suggest that the microorganisms and their metabolites have complex mechanisms of action in regulating Tregs function, which are important for understanding and improving cancer immunotherapy.
4.1.3 Macrophages
Recent studies have revealed that intratumoral microorganisms significantly affect the functional polarization and anti-tumor immune responses of TAMs mainly through metabolic regulation, immune modulation and signaling pathway activation.
Firstly, reshaping the metabolic characteristics of TAMs through microbial metabolites primarily involves SCFAs regulating epigenetic reprogramming. For instance, butyrate suppresses HDACs, upregulates M1-type markers (such as iNOS and IL-12), and promotes TAM polarization toward the anti-tumor M1 phenotype (37, 38). Propionic acid activates G protein-coupled receptor 43 (GPR43), inhibits STAT6 phosphorylation, and blocks IL-4/IL-13-induced M2 polarization (39, 40). Furthermore, other metabolites exert similar effects. For example, E. coli metabolizes tryptophan into kynurenine, which activates the aryl hydrocarbon receptor (AhR). This induces TAMs to express PD-L1 and IL-10, promoting M2 polarization while suppressing CD8+T cell function (41, 42). Secondary bile acids (e.g., deoxycholic acid) inhibit the NF-κB pathway via the farnesoid X receptor (FXR) and the membrane receptor TGR5, reducing proinflammatory cytokine (TNF-α, IL-6) secretion by TAMs and enhancing M2 function (43).
Secondly, microorganisms directly activate pattern recognition receptors (PRRs) to promote the exertion of immune regulatory effects. For instance, lipopolysaccharide (LPS) released by Fusobacterium nucleatum activates the MyD88/NF-κB pathway in TAMs via TLR4, promoting M1 polarization (44, 45). β-glucan from Malassezia binds CLEC7A (Dectin-1), activating the Syk/CARD9 pathway to induce TAMs to secrete IL-1β and CXCL9, recruiting Th1 cells and enhancing antitumor immunity (46). Furthermore, bacterial DNA or mitochondrial DNA activates the cGAS-STING pathway in TAMs, promoting type I interferon (IFN-β) secretion, enhancing M1 polarization, and boosting antigen presentation capacity (47).
Additionally, TAMs polarization is regulated by activating signaling pathways—core hubs in microbe-host interactions—including STAT3/STAT1 balance regulation, the Wnt/β-catenin pathway, and the Hippo-YAP pathway. Research indicates that Bacteroides fragilis activates the IL-10/STAT3 axis by secreting polysaccharides, thereby inhibiting STAT1 phosphorylation, suppressing M1 polarization, and promoting the proangiogenic phenotype of TAMs (2, 48). Butyrate inhibits β-catenin degradation, upregulates Wnt pathway target genes (e.g., CCL2), and promotes the transition of TAMs to immunosuppressive M2-type (49). Clostridium difficile activates the YAP/TAZ signaling pathway, inducing TAMs to express VEGF and arginase-1 (Arg1), thereby promoting tumor angiogenesis and immune evasion (50, 51).
4.1.4 Dendritic cells
Intratumoral microorganisms alter the maturation, metabolism, and functionality of DCs via multiple pathways, leading to a bidirectional modulation—either activation or inhibition—of tumor immunity. Empirical evidence indicates that the activation of DCs by intratumoral microorganisms enhances their antigen-presenting capabilities and the secretion of proinflammatory molecules.
On the one hand, microbes may activate pattern recognition receptors (e.g., TLRs, NOD-like receptors) on the surface of DCs by releasing PAMPs (e.g., LPS, flagellin), thereby promoting the maturation and antigen-presenting capacity of DCs (52, 53). For example, the activation of TLR4 leads to the upregulation of MHC-II-like molecules and co-stimulatory molecules, such as CD80 and CD86, on the surface of DCs, thereby enhancing their proficiency in presenting tumor antigens (28, 54). On the other hand, research indicates that microorganisms or their metabolites can stimulate DCs to produce pro-inflammatory cytokines, such as IL-12 and IFN-γ, thereby activating T-helper 1 (Th1) immune responses and enhancing the anti-tumor efficacy of CD8+T cells (55, 56). The synergistic interaction between IL-12 and IFN-γ further contributes to the persistence and potency of anti-tumor immune responses by modulating immune cell dynamics within the tumor microenvironment (57, 58). Moreover, intratumoral microorganisms can impair DC function by inducing functional depletion and altering their metabolic states. Some intratumoral microbes may impede DC differentiation and maturation by secreting inhibitory factors, such as IL-10 and TGF-β, or by promoting VEGF secretion by tumor cells (56, 59, 60). Additionally, microbial metabolites (e.g., SCFAs) may influence the immune activation capacity of DCs by modulating their metabolic pathways, such as glycolysis and oxidative phosphorylation (61, 62).
4.1.5 Natural killer cells
NK cells play a crucial role in tumor immune surveillance, and their function may be directly or indirectly influenced by microorganisms within the TIME (63). On the one hand, intratumoral microorganisms can directly acton NK cells, enhancing their immune recognition capabilities and restoring the structure and function of NK cell membranes. Literature indicates that specific intratumoral microbes, such as functional bacteria A-gyo, UN-gyo, and AUN isolated from solid tumors, can activate pattern-recognition receptors on NK cells through the release of immunogenic signaling molecules, thereby improving the recognition of tumor cells (64). For instance, these functional bacteria facilitate the formation of immune synapses between NK cells and tumor cells by upregulating the expression of activating receptors, such as NKG2D, on NK cells or by inducing the expression of NKG2D ligands on tumor cells. This interaction leads to the release of granzymes and perforin, which directly kill tumor cells and enhance the cytotoxic efficiency of NK cells against tumor cells (28, 65). At the same time, intratumoral microbes have the potential to restore the sphingolipid content of NK cell membranes and reconstruct the membrane protrusion architecture. This is achieved by modulating the local metabolic milieu, such as through the supplementation of sphingomyelin or the inhibition of sphingomyelinase activity, thereby augmenting the NK cells’ ability to recognize and eliminate tumor cells (66, 67).
In addition, microbes may exert an indirect influence on NK cells by reshaping the TIME and mitigating tumor-induced immunosuppression. Empirical evidence suggests that intratumoral microbes can modulate NK cell function indirectly through the secretion of metabolites or signaling molecules, such as IL-10, which in turn affect the activity of TAMs, Tregs, and DCs within the microenvironment (68–72). For instance, research has demonstrated that synthetic bacteria can enhance the anti-tumor immune response of NK cells by inhibiting neutrophil activity via IL-10 signaling while simultaneously activating CD8+ T cells (66). Additionally, microbes can augment NK cell activity by promoting the secretion of pro-inflammatory cytokines, such as IL-12 and IFN-γ (28). Within the tumor microenvironment, NK cells frequently experience functional suppression due to the upregulation of inhibitory receptors, such as PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or the presence of inhibitory cytokines, including TGF-β and IL-10 (73). Intratumoral microbes may block immunosuppressive signals and restore NK cell killing function through competitive depletion of inhibitory factors or secretion of immunostimulatory molecules (e.g., CpG sequences in bacterial DNA) (28, 66).
4.1.6 Neutrophils
The interaction between intratumoral microbes and neutrophils constitutes a complex and multifaceted process that encompasses various immune responses and cell signaling pathways. Within the cancer microenvironment, neutrophils transcend their traditional role as mere immune cells; they actively contribute to tumor progression and metastasis. The behavior of neutrophils in this context is significantly influenced by the presence of microorganisms. Microbes possess the ability to modulate neutrophils function through direct interaction. For instance, some bacteria can evade immune clearance by delaying the fusion with neutrophils granules, thereby enhancing their survival within these cells (74). Furthermore, the presence of microorganisms can impede T cell infiltration by inducing neutrophils to release extracellular traps (NETs), which form a physical barrier, while simultaneously releasing pro-inflammatory factors that exacerbate inflammation within the TME (75).
4.2 Promotion of anti-tumor immunity by intratumoral microorganisms
Research has demonstrated that intratumoral microorganisms can augment anti-tumor immune responses through various mechanisms, including the modulation of immune system pathways and cancer or immune-related signaling pathways. Within the TME, microorganisms can enhance anti-tumor immunity by activating the cGAS-STING signaling pathway. These intratumoral microbes can stimulate the STING signaling pathway, thereby enhancing the activity of T cells and NK cells, promoting the formation of tertiary lymphoid structures (TLS), and facilitating antigen presentation (76). Bacteroides fragilis produces STING agonists that induce anti-tumor macrophage polarization, promote natural killer cell activation, and enhance interactions with DCs (22). Lactobacillus strains induce cGAS/STING-dependent type I interferon production, activate dendritic cells, and recruit tumor-specific CD8 T cells to the TME (23, 77). Collectively, these mechanisms contribute to the enhancement of the body’s anti-tumor immune response, thereby inhibiting tumor growth and metastasis.
Intratumoral microbes may also modulate immune responses by influencing the TME. Research indicates that these microbes can alter the TME by modulating the infiltration and activity of immune cells, thereby impacting the immune characteristics of the tumor (78). For example, specific microorganisms (Saccharomyces cerevisiae, Pseudomonas pseudomallei, and Streptomyces spp.) present in pancreatic adenocarcinoma (PDAC) tissues enhance the activity of CD8 T cells and granzyme B cells, thereby triggering potent antitumor immune responses and improving overall survival rates (79). The intratumoral microbiome (including Clostridiales strains, EBV, and HBV) induces chemokine production, enhancing CD8 T cell infiltration into tumor tissues and thereby improving survival rates in melanoma patients (80). And microbes may enhance immune surveillance through the secretion of cytokines or chemokines, such as CXCL9/10, which recruit effector immune cells, including CD8+ T cells and dendritic cells, to the tumor site (81). The presence of specific bacterial communities is strongly correlated with the quantity and activity of tumor-infiltrating lymphocytes, suggesting that microorganisms may play a crucial role in regulating the TIME (82).
The presence of intratumoral microbes has been associated with the tumor’s response to therapeutic interventions. Empirical evidence indicates that these microbes can affect the efficacy of immunotherapy by modulating the host’s immune system. Specifically, Microorganisms can modulate the tumor microbiome by directly migrating into tumors and altering the tumor microenvironment, thereby enhancing the efficacy of immune checkpoint inhibitor (ICI) therapy (83). Furthermore, intratumoral microbes may augment the impact of immunotherapy by influencing the function and activity of immune cells (84). In summary, the roles of intratumoral microorganisms in antitumor immunity are complex and multifaceted. They may potentiate antitumor immune responses not only through the direct activation of immune cells but also indirectly by modulating the TME and affecting the outcomes of immunotherapy. These insights provide a crucial theoretical foundation and direction for future research aimed at developing novel cancer immunotherapy strategies (85).
4.3 Intratumoral microorganisms as drivers of immunosuppression
The bacterial communities within tumors exert a dual effect on cancer progression. On one hand, they enhance antitumor immunity, thereby aiding in the resistance against the growth and spread of cancer cells. On the other hand, they promote cancer progression through immunosuppressive mechanisms, creating favorable conditions for the survival and proliferation of cancer cells (86).
Intratumoral microorganisms can shape immunosuppressive microenvironments through complex interactions with the host immune system, thereby influencing the tumor’s capacity for immune evasion (87). Microbial communities within tumor tissues can directly suppress immune cell activity through the production of immunomodulatory molecules, or indirectly facilitate immunosuppression by modifying signaling pathways within host cells (88). For example, bacteria in colorectal cancer secrete IL-17, promoting cancer cell growth by increasing B cell infiltration in tumor tissue (19). Symbiotic bacteria stimulate γδT cells to produce IL-17, enhancing local inflammatory responses in lung cancer and driving tumor progression (89). In PDAC, the microbiota modulates TAMs via TLR signaling pathways, creating an immunosuppressive TME (90).
In addition, intratumoral microorganisms have been shown to facilitate the expansion of immunosuppressive cell populations, contributing to the formation of immunosuppressive TME. Research indicates that these microorganisms can promote the proliferation of cells such as MDSCs, Tregs, and M2-type TAMs (90). For instance, Aspergillus sydowii has been observed to enhance the expansion and activation of MDSCs and TAMs via the IL-1β-mediated β-glucan/Dectin-1/CARD9 signaling pathway. This process results in the inhibition of cytotoxic T-lymphocyte (CTL) function and the aggregation of PD-1+ CD8+ T-cells, thereby contributing to the progression of lung adenocarcinoma (91). Additionally, Fusobacterium nucleatum impairs the anti-tumor activity of NK cells and T cells by interacting with TIGIT through the Fap2 protein (3). Some intratumoral microorganisms (B. fragilis and Fusobacterium) also increase ROS levels or produce metabolites such as short-chain fatty acids, which promote the proliferation of Tregs and MDSCs. These cells, in turn, secrete inhibitory factors like IL-10 and TGF-β, thereby diminishing the antitumor efficacy of effector T cells (92, 93).
In various studies, a decrease in microbial diversity or the enrichment of specific microbial populations is frequently linked to the development of an immunosuppressive TIME. For instance, in esophageal squamous cell carcinoma (ESCC), a high Shannon index, indicative of microbial diversity, has been correlated with diminished PD-L1 upregulation and reduced infiltration of NK cells and activated CTLs. This observation suggests that microbial diversity may facilitate immunosuppression (94). Similarly, in PDAC, intratumoral microbes have been shown to inhibit the differentiation of CD4+ T cells and Th1 cells through the activation of TLRs and to impede the polarization of M1 macrophages (90).
In summary, intratumor microbes play a dual role in regulating the tumor immune microenvironment, both by promoting anti-tumor immune responses and possibly by inducing immunosuppression to promote tumor progression. Future studies should further explore how the properties of intratumor microbes can be exploited to improve the efficacy of tumor immunotherapy.
5 Clinical translation and application potential
The dual role of tumor-associated microbiota and its aforementioned effects on immune cells determine its immense clinical application potential. Several studies have reported the potential of tumor-associated microbiota in translational clinical applications.
5.1 Association with clinical prognosis
The first is that changes in intratumoral microbial diversity correlate with patient prognosis. Studies have shown that microbial alpha diversity in ESCC tumor tissues is significantly lower than in normal tissues, and patients with high bacterial abundance have a worse prognosis (94). The β-diversity characteristics of the intratumoral microbiome exhibit significant differences and can predict the therapeutic efficacy of neoadjuvant chemoimmunotherapy (NACI) efficacy, for example, Streptococcus bacteria accumulate in esophageal squamous cell carcinoma (ESCC), tumor-infiltrating CD8+ T cells increase, and respond well to anti-PD-1 therapy (2). However, the impact of increased or decreased microbial α and β diversity on clinical prognosis varies across different tumor types, and even the same microbial species may exhibit differing effects across distinct tumors.
Secondly, certain specific microbial taxa possess distinct prognostic significance in related tumors. For instance, the presence of Lactobacillus is an independent predictor of diminished survival in ESCC patients (94). Similarly, Fusobacterium nucleatum is linked to adverse prognosis and chemotherapy resistance in esophageal cancer (95). Conversely, an enrichment of Streptococcus is correlated with extended disease-free survival and an improved response to anti-PD-1 therapy in ESCC patients (2).
5.2 Potential applications in tumor therapy
The potential application of intratumoral microorganisms in tumor therapy has attracted much attention in recent years. Research indicates that these microorganisms can impact tumorigenesis, progression, and therapeutic response through various mechanisms. Specifically, intratumoral microbes have the capacity to modulate the immune microenvironment within tumors and affect anti-tumor immune responses, thereby presenting potential novel targets for therapeutic intervention (76).
Current research is concentrated on two primary areas: predicting treatment response and developing intervention strategies targeting the microbiota. For instance, the characterization of intratumoral streptococci has been shown to predict response to NACI in patients with ESCC (2). In locally advanced rectal cancer (LARC), variations in microbial alpha and beta diversity, along with 12 distinct microbial taxa (such as Faecalitalea and Collinsella), have been linked to immune cell infiltration in patients achieving pathologic complete remission (pCR) compared to those not achieving pCR (96). Intervention strategies targeting microbes include colony transplantation, dietary and metabolic modifications, and microbial ablation. The literature indicates that mice receiving fecal microbial transplantation from responders or streptococcal colonization exhibit increased intratumoral CD8+T cell infiltration and enhanced efficacy of anti-PD-1 therapy (2). Additionally, a high-fiber diet has been found to improve immune checkpoint blockade (ICB) efficacy by activating the intratumoral IFN-I-NK-DC axis (22). The elimination of intratumoral microorganisms in PDAC has been shown to remodel the TME, reverse immunosuppression, and enhance the response to immunotherapy (90).
Microbial therapies are undergoing significant advancements, with researchers investigating the potential of employing microorganisms as vehicles for drug delivery and as therapeutic agents. For instance, bacteria can be genetically engineered to express proteins with therapeutic properties, facilitating the targeted delivery of anti-cancer proteins directly within tumor sites (97). Furthermore, bacteria have the capability to impede tumor progression by disrupting the vasculature within tumor tissues and inducing thrombosis, thereby obstructing the nutrient supply to tumor cells (98).
In conclusion, the potential application of intratumoral microbes in tumor therapy provides new perspectives and strategies for cancer treatment. With in-depth studies on the mechanisms of interaction between intratumoral microbes and tumors, more effective cancer therapies are expected to be developed in the future.
6 Summary
Although the role of microbiota in the regulation of TIME has been widely validated, contradictions remain between different studies. For example, microbiota in PDAC can either drive immunosuppression (90) or activate anti-tumor immunity through specific genera (79). Such differences may be related to microbial composition, host genetic background and tumor heterogeneity. Future combination of multi-omics technologies (e.g., single-cell sequencing, spatial transcriptome) is needed to deeply analyze the microbe-TIME interaction network and develop microbiota-based precision therapeutic strategies.
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Author contributions
YT: Writing – review & editing, Conceptualization, Writing – original draft, Methodology. ZX: Writing – review & editing, Resources. ZY: Investigation, Resources, Writing – original draft. LYan: Investigation, Writing – review & editing, Resources. LYang: Methodology, Writing – original draft, Resources. SX: Methodology, Writing – review & editing, Resources. TS: Writing – review & editing, Writing – original draft, Conceptualization.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. (2020) 368:973–80. doi: 10.1126/science.aay9189
2. Wu H, Leng X, Liu Q, Mao T, Jiang T, Liu Y, et al. Intratumoral microbiota composition regulates chemoimmunotherapy response in esophageal squamous cell carcinoma. Cancer Res. (2023) 83:3131–44. doi: 10.1158/0008-5472.CAN-22-2593
3. Xie Y, Xie F, Zhou X, Zhang L, Yang B, Huang J, et al. Microbiota in tumors: from understanding to application. Adv Sci (Weinh). (2022) 9:e2200470. doi: 10.1002/advs.202200470
4. Wu J, Zhang P, Mei W, and Zeng C. Intratumoral microbiota: implications for cancer onset, progression, and therapy. Front Immunol. (2023) 14:1301506. doi: 10.3389/fimmu.2023.1301506
5. Yang L, Li A, Wang Y, and Zhang Y. Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy. Signal Transduct. Tgt. Ther. (2023) 8:35. doi: 10.1038/s41392-022-01304-4
6. Cao Y, Xia H, Tan X, Shi C, Ma Y, Meng D, et al. Intratumoural microbiota: a new frontier in cancer development and therapy. Signal Transduct. Tgt. Ther. (2024) 9:15. doi: 10.1038/s41392-023-01693-0
7. Narunsky-Haziza L, Sepich-Poore GD, Livyatan I, Asraf O, Martino C, Nejman D, et al. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell. (2022) 185:3789–3806.e3717. doi: 10.1016/j.cell.2022.09.005
8. Dougherty MW and Jobin C. Intestinal bacteria and colorectal cancer: etiology and treatment. Gut. Microbes. (2023) 15:2185028. doi: 10.1080/19490976.2023.2185028
10. Ferrari V and Rescigno M. The intratumoral microbiota: friend or foe? Trends Cancer. (2023) 9:472–9. doi: 10.1016/j.trecan.2023.03.005
11. Yang Q, Wang B, Zheng Q, Li H, Meng X, Zhou F, et al. A review of gut microbiota-derived metabolites in tumor progression and cancer therapy. Adv Sci (Weinh). (2023) 10:e2207366. doi: 10.1002/advs.202207366
12. Alam A, Levanduski E, Denz P, Villavicencio HS, Bhatta M, Alhorebi L, et al. Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreatic cancer. Cancer Cell. (2022) 40:153–167.e111. doi: 10.1016/j.ccell.2022.01.003
13. Cullin N, Azevedo Antunes C, Straussman R, Stein-Thoeringer CK, and Elinav E. Microbiome and cancer. Cancer Cell. (2021) 39:1317–41. doi: 10.1016/j.ccell.2021.08.006
14. Zitvogel L, Daillere R, Roberti MP, Routy B, and Kroemer G. Anticancer effects of the microbiome and its products. Nat Rev Microbiol. (2017) 15:465–78. doi: 10.1038/nrmicro.2017.44
15. Zitvogel L, Ma Y, Raoult D, Kroemer G, and Gajewski TF. The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies. Science. (2018) 359:1366–70. doi: 10.1126/science.aar6918
16. Guzelsoy G, Elorza SD, Ros M, Schachtner LT, Hayashi M, Hobson-Gutierrez S, et al. Cooperative nutrient scavenging is an evolutionary advantage in cancer. Nature. (2025) 640:534–42. doi: 10.1038/s41586-025-08588-w
17. Fu A, Yao B, Dong T, Chen Y, Yao J, Liu Y, et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell. (2022) 185:1356–1372.e1326. doi: 10.1016/j.cell.2022.02.027
18. Ait-Zenati F, Djoudi F, Mehelleb D, and Madaoui M. Involvement of the human microbiome in frequent cancers, current knowledge and carcinogenesis mechanisms. Bull Cancer. (2023) 110:776–89. doi: 10.1016/j.bulcan.2023.01.022
19. Triner D, Devenport SN, Ramakrishnan SK, Ma X, Frieler RA, Greenson JK, et al. Neutrophils restrict tumor-associated microbiota to reduce growth and invasion of colon tumors in mice. Gastroenterology. (2019) 156:1467–82. doi: 10.1053/j.gastro.2018.12.003
20. Liu L, Li Q, Chen C, Xin W, Han C, and Hua Z. Oncolytic bacteria VNP20009 expressing IFNbeta inhibits melanoma progression by remodeling the tumor microenvironment. iScience. (2024) 27:109372. doi: 10.1016/j.isci.2024.109372
21. Kim OY, Park HT, Dinh NTH, Choi SJ, Lee J, Kim JH, et al. Bacterial outer membrane vesicles suppress tumor by interferon-gamma-mediated antitumor response. Nat Commun. (2017) 8:626. doi: 10.1038/s41467-017-00729-8
22. Lam KC, Araya RE, Huang A, Chen Q, Di Modica M, Rodrigues RR, et al. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell. (2021) 184:5338–5356.e5321. doi: 10.1016/j.cell.2021.09.019
23. Shi Y, Zheng W, Yang K, Harris KG, Ni K, Xue L, et al. Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling. J Exp Med. (2020) 217:e20192282. doi: 10.1084/jem.20192282
24. Xue C, Chu Q, Zheng Q, Yuan X, Su Y, Bao Z, et al. Current understanding of the intratumoral microbiome in various tumors. Cell Rep Med. (2023) 4:100884. doi: 10.1016/j.xcrm.2022.100884
25. Atreya CE and Turnbaugh PJ. Probing the tumor micro(b)environment. Science. (2020) 368:938–9. doi: 10.1126/science.abc1464
26. Du X, Jie Z, and Zou Q. Microbiota alert: Proteobacteria consume arginine to dampen omental antitumor immunity. Cell Host Microbe. (2024) 32:1045–7. doi: 10.1016/j.chom.2024.05.020
27. Yu AI, Zhao L, Eaton KA, Ho S, Chen J, Poe S, et al. Gut microbiota modulate CD8 T cell responses to influence colitis-associated tumorigenesis. Cell Rep. (2020) 31:107471. doi: 10.1016/j.celrep.2020.03.035
28. Goto Y, Iwata S, Miyahara M, and Miyako E. Discovery of intratumoral oncolytic bacteria toward targeted anticancer theranostics. Adv Sci (Weinh). (2023) 10:e2301679. doi: 10.1002/advs.202301679
29. Feng P, Xue X, Bukhari I, Qiu C, Li Y, Zheng P, et al. Gut microbiota and its therapeutic implications in tumor microenvironment interactions. Front Microbiol. (2024) 15:1287077. doi: 10.3389/fmicb.2024.1287077
30. Jiang SS, Xie YL, Xiao XY, Kang ZR, Lin XL, Zhang L, et al. Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer. Cell Host Microbe. (2023) 31:781–797.e789. doi: 10.1016/j.chom.2023.04.010
31. Rexach JE, Cheng Y, Chen L, Polioudakis D, Lin LC, Mitri V, et al. Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics. Cell. (2024) 187:5753–5774.e5728. doi: 10.1016/j.cell.2024.08.019
32. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. (2013) 504:446–50. doi: 10.1038/nature12721
33. Bender MJ, McPherson AC, Phelps CM, Pandey SP, Laughlin CR, Shapira JH, et al. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell. (2023) 186:1846–1862.e1826. doi: 10.1016/j.cell.2023.03.011
34. Campesato LF, Budhu S, Tchaicha J, Weng CH, Gigoux M, Cohen IJ, et al. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. Nat Commun. (2020) 11:4011. doi: 10.1038/s41467-020-17750-z
35. Iida H, Tohno M, Islam MA, Sato N, Kobayashi H, Albarracin L, et al. Paraimmunobiotic bifidobacteria modulate the expression patterns of peptidoglycan recognition proteins in porcine intestinal epitheliocytes and antigen presenting cells. Cells. (2019) 8:891. doi: 10.3390/cells8080891
36. Kim Y, Park JY, Kim H, and Chung DK. Differential role of lipoteichoic acids isolated from Staphylococcus aureus and Lactobacillus plantarum on the aggravation and alleviation of atopic dermatitis. Microb Pathog. (2020) 147:104360. doi: 10.1016/j.micpath.2020.104360
37. Lobel L and Garrett WS. Butyrate makes macrophages “Go nuclear” against bacterial pathogens. Immunity. (2019) 50:275–8. doi: 10.1016/j.immuni.2019.01.015
38. Schulthess J, Pandey S, Capitani M, Rue-Albrecht KC, Arnold I, Franchini F, et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity. (2019) 50:432–445.e437. doi: 10.1016/j.immuni.2018.12.018
39. Moonwiriyakit A, Yimnual C, Noitem R, Dinsuwannakol S, Sontikun J, Kaewin S, et al. GPR120/FFAR4 stimulation attenuates airway remodeling and suppresses IL-4- and IL-13-induced airway epithelial injury via inhibition of STAT6 and Akt. BioMed Pharmacother. (2023) 168:115774. doi: 10.1016/j.biopha.2023.115774
40. Weng SY, Wang X, Vijayan S, Tang Y, Kim YO, Padberg K, et al. IL-4 receptor alpha signaling through macrophages differentially regulates liver fibrosis progression and reversal. EBioMedicine. (2018) 29:92–103. doi: 10.1016/j.ebiom.2018.01.028
41. Takenaka MC, Gabriely G, Rothhammer V, Mascanfroni ID, Wheeler MA, Chao CC, et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat Neurosci. (2019) 22:729–40. doi: 10.1038/s41593-019-0370-y
42. Wen ZF, Liu H, Gao R, Zhou M, Ma J, Zhang Y, et al. Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1. J Immunother Cancer. (2018) 6:151. doi: 10.1186/s40425-018-0452-5
43. Chavez-Talavera O, Tailleux A, Lefebvre P, and Staels B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology. (2017) 152:1679–1694.e1673. doi: 10.1053/j.gastro.2017.01.055
44. Chen T, Li Q, Wu J, Wu Y, Peng W, Li H, et al. Fusobacterium nucleatum promotes M2 polarization of macrophages in the microenvironment of colorectal tumours via a TLR4-dependent mechanism. Cancer Immunol Immunother. (2018) 67:1635–46. doi: 10.1007/s00262-018-2233-x
45. Hu L, Liu Y, Kong X, Wu R, Peng Q, Zhang Y, et al. Fusobacterium nucleatum facilitates M2 macrophage polarization and colorectal carcinoma progression by activating TLR4/NF-kappaB/S100A9 cascade. Front Immunol. (2021) 12:658681. doi: 10.3389/fimmu.2021.658681
46. Liu NN, Yi CX, Wei LQ, Zhou JA, Jiang T, Hu CC, et al. The intratumor mycobiome promotes lung cancer progression via myeloid-derived suppressor cells. Cancer Cell. (2023) 41:1927–1944.e1929. doi: 10.1016/j.ccell.2023.08.012
47. Dvorkin S, Cambier S, Volkman HE, and Stetson DB. New frontiers in the cGAS-STING intracellular DNA-sensing pathway. Immunity. (2024) 57:718–30. doi: 10.1016/j.immuni.2024.02.019
48. Wang N, Wu S, Huang L, Hu Y, He X, He J, et al. Intratumoral microbiome: implications for immune modulation and innovative therapeutic strategies in cancer. J BioMed Sci. (2025) 32:23. doi: 10.1186/s12929-025-01117-x
49. Zhang F, Li P, Liu S, Yang M, Zeng S, Deng J, et al. beta-Catenin-CCL2 feedback loop mediates crosstalk between cancer cells and macrophages that regulates breast cancer stem cells. Oncogene. (2021) 40:5854–65. doi: 10.1038/s41388-021-01986-0
50. Kim J, Kim YH, Kim J, Park DY, Bae H, Lee DH, et al. YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J Clin Invest. (2017) 127:3441–61. doi: 10.1172/JCI93825
51. Zhang Y, Fan Y, Jing X, Zhao L, Liu T, Wang L, et al. OTUD5-mediated deubiquitination of YAP in macrophage promotes M2 phenotype polarization and favors triple-negative breast cancer progression. Cancer Lett. (2021) 504:104–15. doi: 10.1016/j.canlet.2021.02.003
52. Chow KT, Gale M Jr., and Loo YM. RIG-I and other RNA sensors in antiviral immunity. Annu Rev Immunol. (2018) 36:667–94. doi: 10.1146/annurev-immunol-042617-053309
53. Li D and Wu M. Pattern recognition receptors in health and diseases. Signal Transduct. Tgt. Ther. (2021) 6:291. doi: 10.1038/s41392-021-00687-0
54. Thibodeau J, Bourgeois-Daigneault MC, and Lapointe R. Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy. Oncoimmunology. (2012) 1:908–16. doi: 10.4161/onci.21205
55. Garris CS, Arlauckas SP, Kohler RH, Trefny MP, Garren S, Piot C, et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-gamma and IL-12. Immunity. (2018) 49:1148–1161.e1147. doi: 10.1016/j.immuni.2018.09.024
56. Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell. (2014) 26:623–37. doi: 10.1016/j.ccell.2014.09.006
57. Haabeth OA, Lorvik KB, Hammarstrom C, Donaldson IM, Haraldsen G, Bogen B, et al. Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer. Nat Commun. (2011) 2:240. doi: 10.1038/ncomms1239
58. Haabeth OA, Lorvik KB, Yagita H, Bogen B, and Corthay A. Interleukin-1 is required for cancer eradication mediated by tumor-specific Th1 cells. Oncoimmunology. (2016) 5:e1039763. doi: 10.1080/2162402X.2015.1039763
59. Rahma OE and Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res. (2019) 25:5449–57. doi: 10.1158/1078-0432.CCR-18-1543
60. Terra M, Oberkampf M, Fayolle C, Rosenbaum P, Guillerey C, Dadaglio G, et al. Tumor-derived TGFbeta alters the ability of plasmacytoid dendritic cells to respond to innate immune signaling. Cancer Res. (2018) 78:3014–26. doi: 10.1158/0008-5472.CAN-17-2719
61. Kim M, Qie Y, Park J, and Kim CH. Gut microbial metabolites fuel host antibody responses. Cell Host Microbe. (2016) 20:202–14. doi: 10.1016/j.chom.2016.07.001
62. Mann ER, Lam YK, and Uhlig HH. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat Rev Immunol. (2024) 24:577–95. doi: 10.1038/s41577-024-01014-8
63. Wu SY, Fu T, Jiang YZ, and Shao ZM. Natural killer cells in cancer biology and therapy. Mol Cancer. (2020) 19:120. doi: 10.1186/s12943-020-01238-x
64. Kepp O, Marabelle A, Zitvogel L, and Kroemer G. Oncolysis without viruses - inducing systemic anticancer immune responses with local therapies. Nat Rev Clin Oncol. (2020) 17:49–64. doi: 10.1038/s41571-019-0272-7
65. Mager LF, Burkhard R, Pett N, Cooke NCA, Brown K, Ramay H, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. (2020) 369:1481–9. doi: 10.1126/science.abc3421
66. Chang Z, Guo X, Li X, Wang Y, Zang Z, Pei S, et al. Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization. Cell. (2025) 188:1842–1857.e20. doi: 10.1016/j.cell.2025.02.002
67. Wu N, Song H, and Veillette A. Plasma membrane lipid scrambling causing phosphatidylserine exposure negatively regulates NK cell activation. Cell Mol Immunol. (2021) 18:686–97. doi: 10.1038/s41423-020-00600-9
68. Arner EN and Rathmell JC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell. (2023) 41:421–33. doi: 10.1016/j.ccell.2023.01.009
69. Bottcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, et al. NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. Cell. (2018) 172:1022–1037.e1014. doi: 10.1016/j.cell.2018.01.004
70. Ringel AE, Drijvers JM, Baker GJ, Catozzi A, Garcia-Canaveras JC, Gassaway BM, et al. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell. (2020) 183:1848–1866.e1826. doi: 10.1016/j.cell.2020.11.009
71. Sivick KE, Desbien AL, Glickman LH, Reiner GL, Corrales L, Surh NH, et al. Magnitude of therapeutic STING activation determines CD8(+) T cell-mediated anti-tumor immunity. Cell Rep. (2018) 25:3074–3085.e3075. doi: 10.1016/j.celrep.2018.11.047
72. Wang YA, Li XL, Mo YZ, Fan CM, Tang L, Xiong F, et al. Effects of tumor metabolic microenvironment on regulatory T cells. Mol Cancer. (2018) 17:168. doi: 10.1186/s12943-018-0913-y
73. Budhu S, Schaer DA, Li Y, Toledo-Crow R, Panageas K, Yang X, et al. Blockade of surface-bound TGF-beta on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci Signal. (2017) 10:eaak9702. doi: 10.1126/scisignal.aak9702
74. Johnson MB and Criss AK. Neisseria gonorrhoeae phagosomes delay fusion with primary granules to enhance bacterial survival inside human neutrophils. Cell Microbiol. (2013) 15:1323–40. doi: 10.1111/cmi.12117
75. Cacciotto C and Alberti A. Eating the enemy: mycoplasma strategies to evade neutrophil extracellular traps (NETs) promoting bacterial nucleotides uptake and inflammatory damage. Int J Mol Sci. (2022) 23:15030. doi: 10.3390/ijms232315030
76. Zhang L and Yu L. The role of the microscopic world: Exploring the role and potential of intratumoral microbiota in cancer immunotherapy. Med (Balt). (2024) 103:e38078. doi: 10.1097/MD.0000000000038078
77. Si W, Liang H, Bugno J, Xu Q, Ding X, Yang K, et al. Lactobacillus rhamnosus GG induces cGAS/STING- dependent type I interferon and improves response to immune checkpoint blockade. Gut. (2022) 71:521–33. doi: 10.1136/gutjnl-2020-323426
78. Xu J, Cheng M, Liu J, Cui M, Yin B, and Liang J. Research progress on the impact of intratumoral microbiota on the immune microenvironment of Malignant tumors and its role in immunotherapy. Front Immunol. (2024) 15:1389446. doi: 10.3389/fimmu.2024.1389446
79. Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. (2019) 178:795–806.e712. doi: 10.1016/j.cell.2019.07.008
80. Zhu G, Su H, Johnson CH, Khan SA, Kluger H, and Lu L. Intratumour microbiome associated with the infiltration of cytotoxic CD8+ T cells and patient survival in cutaneous melanoma. Eur J Cancer. (2021) 151:25–34. doi: 10.1016/j.ejca.2021.03.053
81. Schurch CM, Bhate SS, Barlow GL, Phillips DJ, Noti L, Zlobec I, et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell. (2020) 182:1341–1359.e1319. doi: 10.1016/j.cell.2020.07.005
82. Pratap Singh R, Kumari N, Gupta S, Jaiswal R, Mehrotra D, Singh S, et al. Intratumoral microbiota changes with tumor stage and influences the immune signature of oral squamous cell carcinoma. Microbiol Spectr. (2023) 11:e0459622. doi: 10.1128/spectrum.04596-22
83. Wang W, Fan J, Zhang C, Huang Y, Chen Y, Fu S, et al. Targeted modulation of gut and intra-tumor microbiota to improve the quality of immune checkpoint inhibitor responses. Microbiol Res. (2024) 282:127668. doi: 10.1016/j.micres.2024.127668
84. Roesel R, Strati F, Basso C, Epistolio S, Spina P, Djordjevic J, et al. Combined tumor-associated microbiome and immune gene expression profiling predict response to neoadjuvant chemo-radiotherapy in locally advanced rectal cancer. Oncoimmunology. (2025) 14:2465015. doi: 10.1080/2162402X.2025.2465015
85. Zhang L, Duan X, Zhao Y, Zhang D, and Zhang Y. Implications of intratumoral microbiota in tumor metastasis: a special perspective of microorganisms in tumorigenesis and clinical therapeutics. Front Immunol. (2025) 16:1526589. doi: 10.3389/fimmu.2025.1526589
86. Sepich-Poore GD, Carter H, and Knight R. Intratumoral bacteria generate a new class of therapeutically relevant tumor antigens in melanoma. Cancer Cell. (2021) 39:601–3. doi: 10.1016/j.ccell.2021.04.008
87. Libertucci J and Young VB. The role of the microbiota in infectious diseases. Nat Microbiol. (2019) 4:35–45. doi: 10.1038/s41564-018-0278-4
88. Mathis D and Benoist C. Microbiota and autoimmune disease: the hosted self. Cell Host Microbe. (2011) 10:297–301. doi: 10.1016/j.chom.2011.09.007
89. Jin C, Lagoudas GK, Zhao C, Bullman S, Bhutkar A, Hu B, et al. Commensal Microbiota Promote Lung Cancer Development via gammadelta T Cells. Cell. (2019) 176:998–1013.e1016. doi: 10.1016/j.cell.2018.12.040
90. Pushalkar S, Hundeyin M, Daley D, Zambirinis CP, Kurz E, Mishra A, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. (2018) 8:403–16. doi: 10.1158/2159-8290.CD-17-1134
91. Liu NN, Yi CX, Wei LQ, Zhou JA, Jiang T, Hu CC, et al. The intratumor mycobiome promotes lung cancer progression via myeloid-derived suppressor cells. Cancer Cell. (2024) 42:318–22. doi: 10.1016/j.ccell.2024.01.005
92. Gil Z and Billan S. Crosstalk between macrophages and endothelial cells in the tumor microenvironment. Mol Ther. (2021) 29:895–6. doi: 10.1016/j.ymthe.2021.02.002
93. Lv D, Fei Y, Chen H, Wang J, Han W, Cui B, et al. Crosstalk between T lymphocyte and extracellular matrix in tumor microenvironment. Front Immunol. (2024) 15:1340702. doi: 10.3389/fimmu.2024.1340702
94. Zhang S, Zhang S, Ma X, Zhan J, Pan C, Zhang H, et al. Intratumoral microbiome impacts immune infiltrates in tumor microenvironment and predicts prognosis in esophageal squamous cell carcinoma patients. Front Cell Infect Microbiol. (2023) 13:1165790. doi: 10.3389/fcimb.2023.1165790
95. Yamamura K, Baba Y, Nakagawa S, Mima K, Miyake K, Nakamura K, et al. Human microbiome fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin Cancer Res. (2016) 22:5574–81. doi: 10.1158/1078-0432.CCR-16-1786
96. Sun L, Qu J, Ke X, Zhang Y, Xu H, Lv N, et al. Interaction between intratumoral microbiota and tumor mediates the response of neoadjuvant therapy for rectal cancer. Front Microbiol. (2023) 14:1229888. doi: 10.3389/fmicb.2023.1229888
97. Mukai H, Takahashi M, and Watanabe Y. Potential usefulness of Brevibacillus for bacterial cancer therapy: intratumoral provision of tumor necrosis factor-alpha and anticancer effects. Cancer Gene Ther. (2018) 25:47–57. doi: 10.1038/s41417-017-0009-7
Keywords: tumor microenvironment, intratumoral microbiota, tumor immune microenvironment, immune cells, immunosuppression, antitumor immunity
Citation: Tingting Y, Xiaoling Z, Yu Z, Yan L, Yang L, Xueqin S and Shikai T (2025) Interaction of intratumoral microbiota with the tumor immune microenvironment and its impact on cancer progression. Front. Oncol. 15:1609889. doi: 10.3389/fonc.2025.1609889
Received: 11 April 2025; Accepted: 21 November 2025; Revised: 30 October 2025;
Published: 10 December 2025.
Edited by:
Stephen Blake, South Australian Health and Medical Research Institute (SAHMRI), AustraliaReviewed by:
Brunella Posteraro, Catholic University of the Sacred Heart, ItalyAnna Fialová, SOTIO a.s., Czechia
Nikhilesh Joardar, Dr. Vishwanath Karad MIT World Peace University, India
Copyright © 2025 Tingting, Xiaoling, Yu, Yan, Yang, Xueqin and Shikai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Tang Shikai, Mjc1OTE3MjI3QHFxLmNvbQ==