The preservation of mucosal homeostasis is fundamentally underpinned by the differentiation of forkhead box protein P3 (Foxp3) ⁺ Tregs. It is imperative to delineate this state of physiological tolerance—essential for averting autoimmunity and excessive inflammation—from the pathological immunosuppression that pervades the TME. Mechanistically, SCFAs, particularly butyrate, function as HDACs inhibitors. By facilitating histone hyperacetylation at the Foxp3 locus, butyrate epigenetically stabilizes the Treg lineage and amplifies the secretion of the anti-inflammatory cytokine IL-10. This molecular orchestration concurrently mitigates NF-κB-driven inflammation and safeguards against autoimmune pathology (29–31, 43, 44).

Crucially, microbial metabolites do not merely induce suppression; they also bolster anti-tumor immunity. Through distinct epigenetic reprogramming pathways, SCFAs have been shown to enhance the metabolic fitness, cytotoxicity, and memory function of CD8⁺ T cells, thereby strengthening long-term immune surveillance (45).

Additionally, SCFAs signaling via G-protein-coupled receptor (GPR)-43 on neutrophils and T cells further fine-tunes immune recruitment and cytokine profiles (31). The integrity of the adaptive immune barrier, particularly the function of intraepithelial lymphocytes (IELs), is modulated by ligand availability for the Aryl Hydrocarbon Receptor (AhR). Microbial derivatives of tryptophan (indole compounds) act as AhR agonists, which are crucial for stabilizing the Th17/Treg balance and reinforcing the intestinal and vaginal barriers against aberrant adaptive activation (46–48).

The gut microbiota plays a crucial role in the regulation of immune cell functions through its metabolic products. Microbial metabolites are instrumental in determining the fate of innate immune cells; they can modulate the polarization of macrophages and facilitate the differentiation into the M1 phenotype, characterized by its anti-tumor activity. Furthermore, these metabolites can enhance the cytotoxic capabilities of natural killer (NK) cells and promote the maturation of dendritic cells (DCs), thereby improving their antigen-presenting efficacy and establishing a foundation for the initiation of adaptive immune responses (64). In terms of adaptive immunity, this regulatory process exhibits a high degree of context dependence: SCFAs are capable of both promoting the differentiation of Tregs to maintain immune tolerance and enhancing the functionality of effector T cells within TME through specific mechanisms (43, 45). This underscores the ability of the microbiota to achieve precise immune modulation based on microenvironmental signals (Figure 3).

In a state of eubiosis, the microbiota functions as a critical “endogenous adjuvant,” mediating a state of heightened immunological alertness that is essential for the detection and elimination of nascent malignant cells. This tumor-suppressive capacity is orchestrated through advanced immunological mechanisms that transcend simple immune activation. Effective tumor eradication necessitates CD8⁺ T cells with high metabolic adaptability. Commensal-derived metabolites, particularly butyrate, have been shown to enhance mitochondrial oxidative phosphorylation in CD8⁺ cytotoxic T lymphocytes (CTLs). This metabolic reprogramming mitigates premature exhaustion and preserves a “stem-like” progenitor phenotype (TCF1⁺ CD8⁺), a prerequisite for sustained anti-tumor cytotoxicity and responsiveness to immune checkpoint blockade (45, 65, 66). The microbiota sets the activation threshold for the innate immune system. Tonic commensal signals engage the cGAS-STING pathway to induce basal Type I interferon signaling, which “licenses” NK cells and macrophages. This ensures innate effectors remain poised to rapidly eliminate major histocompatibility complex (MHC)-I-deficient tumor variants that typically escape T-cell recognition (67). Specific commensal bacteria express surface antigens sharing sequence homology with tumor-associated antigens (TAAs). Through molecular mimicry, these microbial antigens prime cross-reactive CD8⁺ T cells within gut-associated lymphoid tissue (GALT). These educationally primed T cells subsequently traffic to distal reproductive tissues to exert specific cytotoxicity, functioning effectively as an autologous cancer vaccine (68). Finally, a healthy microbiome facilitates the neogenesis of tertiary lymphoid structures (TLS) within the reproductive tract mucosa. Mechanistically, commensal-derived signals stimulate stromal cells and DCs to secrete lymphoid chemokines, particularly CXCL13, which recruits CXCR5⁺ B cells and T follicular helper (Tfh) cells to the tumor site. Within these organized ectopic lymphoid aggregates, germinal center-like reactions occur, facilitating in situ B-cell somatic hypermutation and the generation of plasma cells producing tumor-specific antibodies. By establishing these local hubs for antigen presentation and lymphocyte maturation, the microbiota transforms the TME from “cold” to “hot”, a feature strongly correlated with favorable prognosis and enhanced responsiveness to immunotherapy in gynecological malignancies (64, 69).

In stark contrast to physiological immune tolerance, which actively maintains host–microbiota symbiosis under homeostatic conditions, dysbiosis drives a pathological immunosuppressive state that facilitates tumor immune escape. This breakdown of gut microbiota homeostasis unleashes its pro-inflammatory and carcinogenic potential primarily through two pivotal mechanisms. Firstly, LPS serves not only as a crucial structural element maintaining the integrity of the Gram-negative bacterial outer membrane but also as the most distinctive and biologically active microbial molecule detectable within the host circulatory system. The pathogenesis of systemic inflammation in this context is inextricably linked to the ‘LPS/TLR4 axis’. The process initiates with the compromise of intestinal mucosal integrity, often referred to as ‘leaky gut,’ which permits the aberrant translocation of gut-derived LPS from the intestinal lumen into the vascular system. Once in circulation, LPS is recognized by the innate immune system with high specificity. It acts as a canonical ligand for the TLR4, a transmembrane receptor widely expressed on innate immune cells like macrophages and dendritic cells. The ligation of TLR4 mobilizes the canonical NF-κB signaling pathway, a master regulator of inflammation. The subsequent activation of NF-κB promotes the transcription of a vast array of inflammatory mediators, thereby shifting the host’s physiological state from homeostasis to one of chronic, low-grade systemic inflammation—a condition increasingly recognized as a foundational driver of metabolic disorders (45, 70–75). Crucially, this sustained inflammatory milieu acts as a potent driver of carcinogenesis. By inducing oxidative stress and accumulating reactive oxygen species (ROS), it promotes genomic instability and aberrant epithelial proliferation. Concurrently, the release of specific chemokines within this microenvironment orchestrates the infiltration of immunosuppressive populations—notably MDSCs and Tregs—thereby establishing a permissive TME that facilitates immune evasion (76). Researches have shown that immune cells activated by LPS produce reactive oxygen species, and the oxidative DNA damage caused by this may induce tumorigenic mutations (77–79). Secondly, dysbiosis facilitates the synergistic activation of direct carcinogenic cascades, extending its pathological impact far beyond the mere induction of an inflammatory milieu. This causal relationship is substantiated by pivotal fecal microbiota transplantation (FMT) experiments utilizing gnotobiotic murine models. Specifically, the inoculation of germ-free mice with fecal samples from colorectal cancer patients effectively recapitulates the tumorigenic phenotype observed in donors. This process is characterized by aberrant epithelial hyperplasia, profound neovascularization, and the constitutive activation of canonical oncogenic pathways, most notably the Wnt/β-catenin signaling axis. Concomitantly, the induction of a robust Th1/Th17-mediated inflammatory response highlights a critical pathological synergy: microbial communities not only drive genetic instability but also orchestrate immune dysregulation, thereby collectively propelling the neoplastic trajectory (80–83).

The profound biological impact of the microbiota is most clinically consequential in the realm of cancer immunotherapy, where it has emerged as a key determinant of therapeutic heterogeneity. Extensive multi-cohort studies have revealed that the gut microbiome composition distinctly stratifies patients into ‘responders’ and ‘non-responders’ to immune checkpoint blockade (ICB). Specifically, a high baseline abundance of immunomodulatory commensals—most notably Faecalibacterium prausnitzii and Akkermansia muciniphila—is strongly positively correlated with favorable clinical outcomes following programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) inhibition. Moving beyond mere correlation, FMT experiments have provided elegant causal evidence: transferring stool from responding patients into germ-free mice confers distinct antitumor immunity and restores sensitivity to ICB therapy. Mechanistically, these beneficial microbes are hypothesized to potentiate the therapeutic efficacy by secreting bioactive metabolites and engaging pattern recognition receptors. This interaction primes dendritic cells and facilitates the recruitment of cytotoxic CD8⁺ T cells into the tumor microenvironment, thereby overcoming resistance and amplifying the host’s anti-tumor immune response (64, 84).

Mechanistically, this therapeutic synergy is underpinned by the microbiota’s capacity to augment the antigen-presenting machinery of DCs (85). By promoting DCs maturation and the secretion of pro-inflammatory cytokines (e.g., IL-12), these commensals orchestrate the chemokine-driven recruitment (via CXCL9/CXCL10) and subsequent activation of cytotoxic CD8⁺ T lymphocytes within the tumor bed (84, 86). This cascade effectively reprograms the local immune landscape, converting an immunosuppressive, ‘cold’ tumor microenvironment into an inflamed, anti-tumor phenotype (64, 87). This finding reveals the significant translational potential of regulating the microbiota through strategies such as probiotics, prebiotics, or FMT to improve the efficacy of immunotherapy.

The intestinal microbiota functions as a pivotal regulator of estrogen homeostasis via the enterohepatic circulation, a process governed largely by bacterial β-glucuronidase activity. Following hepatic Phase II metabolism, estrogens are conjugated with glucuronic acid to form hydrophilic, inactive metabolites intended for biliary excretion. However, upon reaching the distal intestine, this elimination pathway is frequently intercepted by the ‘estrobolome’—specifically, bacterial taxa such as Clostridium and Bacteroides that express high levels of β-glucuronidase. These enzymes catalyze the hydrolysis of the glycosidic bond within conjugated estrogens, effectively deconjugating them to liberate biologically active aglycones. Consequently, these reactivated estrogens are salvaged via reabsorption across the intestinal mucosa, entering the portal circulation to substantially augment the systemic hormonal burden and bioavailability (33–36, 93). This intricate process, governed by specialized microbial genes—collectively termed the estrogen metagenome or estrobolome—represents a pivotal mechanism in maintaining the host’s estrogen homeostasis.

Gut dysbiosis represents a pathological deviation from homeostasis that fundamentally disrupts hormonal metabolism. As demonstrated by Fuhrman et al., this state is clinically characterized by a reduction in microbial αdiversity and a concomitant shift in metabolic function, showing a strong correlation with elevated systemic estrogen levels in postmenopausal women (94). Specifically, the pathological enrichment of taxa possessing high β-glucuronidase activity acts as a catalytic driver for hormonal dysregulation. According to structural biology studies by Ervin et al., these bacterial enzymes exhibit specific loop structures that efficiently bind and hydrolyze conjugated estrogens (36). This aberrant surge in enzymatic activity amplifies the enterohepatic salvage of free estrogens, effectively reversing hepatic clearance and establishing a state of persistent systemic hyperestrogenemia. Consequently, hormone-sensitive distal tissues are chronically subjected to supraphysiological estrogen concentrations. This persistent ligand availability drives the constitutive activation of ERs, initiating a pathogenic signaling cascade. In the context of gynecological malignancies, such as endometrial and ovarian cancers, this “hormonal forcing” fuels downstream mitogenic pathways (e.g., PI3K/Akt and MAPK/ERK) and upregulates pro-proliferative genes like Cyclin D1 and MYC. As elucidated by Walther-António et al., such microbiome-driven hormonal alterations are not merely systemic but are intrinsically linked to the etiology of endometrial hyperplasia and carcinogenesis (95). This creates a permissive microenvironment defined by unchecked cellular proliferation and resistance to apoptosis, providing fertile ground for malignant initiation and clonal expansion (33, 35, 36, 94, 95). Therefore, individuals exhibiting a specific “high-risk” estrobolome signature—characterized by an expanded capacity for estrogen reactivation—face a significantly increased susceptibility to hormone-dependent malignancies. This underscores the critical role of the gut microbiome as an extrinsic endocrine regulator that dictates the host’s cumulative exposure to bioactive estrogens. In summary, the microbiome, alongside its metabolic repertoire, constitutes a complex, multifaceted regulatory nexus that fundamentally orchestrates the pathophysiology of the reproductive tract.

The cervicovaginal microenvironment functions as a primary gatekeeper against viral acquisition. In a state of optimal health—often classified as CST I—the niche is dominated by Lactobacillus crispatus. Current mechanistic evidence suggests that L. crispatus confers colonization resistance not merely through acidification, but via the stereospecific production of D-lactic acid. Unlike its L-isomer, D-lactic acid has been shown in preclinical models to downregulate extracellular matrix metalloproteinase inducer (EMMPRIN) and inhibit matrix metalloproteinase-8 (MMP-8). This stereospecific regulation reinforces the viscosity of cervicovaginal mucus and preserves the integrity of epithelial tight junctions, creating a robust physicochemical “firewall” that physically impedes viral access to basal keratinocytes (101, 103–105). In contrast, vaginal dysbiosis (CST IV), characterized by a high-diversity polymicrobial biofilm of obligate anaerobes, represents a critical ecological shift associated with viral pathogenesis. It is imperative to rigorously distinguish epidemiological correlation from etiological causation: while extensive longitudinal human cohorts have established a robust statistical link between CST IV and increased HPV acquisition, definitively proving that dysbiosis functions as a primary driver rather than a consequence of infection remains challenging. However, in vitro investigations provide a biologically plausible rationale for this association, proposing a mechanism of Enzymatic Barrier Breach. Dysbiotic pathobionts—notably Gardnerella vaginalis—secrete high concentrations of sialidases and mucinases. These enzymes hydrolyze the terminal sialic acid residues on host mucins, dismantling the gel-forming capacity of the mucus. This enzymatic degradation effectively “unlocks” the physicochemical firewall, physically facilitating the penetration of HPV virions to their target receptors (98–101, 103, 104, 106–109). Beyond physical barrier disruption, dysbiosis triggers a local inflammatory response characterized by elevated IL-1β, IL-6, and TNF-α (109). Paradoxically, this non-specific inflammation does not clear the virus; instead, it creates a “permissive microenvironment” by recruiting activated immune cells that serve as targets for coinfections or inducing ROS. These ROS contribute to host DNA damage, thereby synergizing with HPV oncogenes (E6/E7) to promote genomic instability (108, 110). Recent advancements have underscored that “Lactobacillus-dominance” is not universally protective; the immunological outcome is strictly dictated by species-specific functional profiles. L. crispatus relies on the unique D-lactic acid-mediated suppression of EMMPRIN/MMP-8 to maintain barrier integrity (105). In stark contrast, L. iners-dominance (CST III) represents an ecologically ambiguous state. Unlike L. crispatus, L. iners primarily produces the L-lactic acid isomer, which is ineffective at downregulating EMMPRIN, resulting in a comparatively “leaky” mucosal barrier. Furthermore, L. iners expresses inerolysin, a cholesterol-dependent cytolysin (CDC). This pore-forming toxin may compromise epithelial membrane integrity and induce sub-clinical inflammation. Consequently, L. iners is epidemiologically associated with significantly higher rates of HPV recurrence, highlighting it as a marker of mucosal vulnerability rather than stability (111–113). In the specific niche of the local cervical TME, the enrichment of specific anaerobic genera—notably Sneathia, Fusobacterium, and Porphyromonas—constitutes a consistent microbial biosignature of malignancy. However, interpreting this shift from a healthy Lactobacillus-dominant state presents a critical epistemological challenge. Current mechanistic models propose a bidirectional relationship: these taxa may function as active ‘drivers’ of tumorigenesis by generating immunomodulatory oncometabolites—such as succinate (which stabilizes HIF-1α) and polyamines—or by engaging immune checkpoints (e.g., Fusobacterium-TIGIT interaction). Conversely, they may exist merely as opportunistic ‘passengers’ that exploit the hypoxic, necrotic niche created by the tumor (‘tumorotropic colonization’). Given this etiological complexity, therapeutic strategies aiming for local ecological restoration—specifically vaginal microbiota transplantation (VMT)—are currently classified as investigational approaches. While supported by strong preclinical rationale, rigorous randomized controlled trials (RCTs) are urgently required to determine whether re-establishing physiological L. crispatus dominance translates into tangible oncological benefits (108, 110, 114).

Vaginal microbiome dysbiosis is not merely a background factor for the occurrence of cervical cancer; rather, it promotes the development of cervical cancer through various interrelated biological mechanisms (101, 103, 104).

The dysregulation of cervical microecology is often marked by a diminishment in protective lactobacilli and an aberrant proliferation of various anaerobic bacteria. This imbalance serves as a primary catalyst for chronic local inflammation (115, 116). The pathogen-associated molecular patterns (PAMPs) released by these anaerobic organisms effectively engage pattern recognition receptors (PRRs) present on the surfaces of epithelial and immune cells, initiating a cascade of downstream inflammatory signaling pathways, notably including NF-κB (117). This activation culminates in the persistent release of a hierarchically organized cytokine network: pro-inflammatory cytokines, such as IL-1β, TNF-α, IL-6, drive chronic inflammation and tissue damage, while chemotactic cytokines, such as interferon-inducible protein-10 (IP-10/CXCL10) and macrophage inflammatory protein-1α (MIP-1α/CCL3), actively recruit leukocytes to the lesion site, perpetuating the inflammatory loop (115–117). Together, these cytokine classes cooperate to generate a paradoxical microenvironment characterized by simultaneous inflammation and immune tolerance. This chronic inflammatory milieu not only invites substantial infiltration of immune cells but also enables the inflammatory mediators to foster abnormal cell proliferation, impede apoptosis, and heighten genomic instability. Consequently, this creates a conducive environment for the carcinogenesis of cells infected by HPV.

The progression from persistent viral infection to invasive malignancy necessitates the active subversion of local immune surveillance, a process facilitated by dysbiosis through the construction of a multi-layered immunosuppressive network. A pivotal evasion mechanism involves the direct engagement of inhibitory receptors on cytotoxic cells; specifically, Fusobacterium nucleatum actively subverts antitumor immunity by expressing the surface protein Fap2, which binds to the T cell immunoreceptor with Ig and ITIM domains (TIGIT) on NK and T cells. Unlike physiological regulatory mechanisms, this bacterial engagement triggers an aberrant inhibitory signal acting as a potent ‘off-switch.’ By directly attenuating cytotoxic granule release, F. nucleatumcreates an immunosuppressive niche that functionally paralyzes the host’s ability to eliminate HPV-infected cells (118, 119). Concurrently, the dysbiotic microenvironment orchestrates a detrimental shift in the local cytokine milieu, where the enhanced secretion of immunosuppressive cytokines—notably transforming growth factor-beta 1 (TGF-β1) and IL-10—promotes the differentiation of Tregs while suppressing antiviral effector T cells. This cytokine profile drives a “functional skewing” from a protective Th1 response (required for viral clearance) to a permissive Th2/Treg-dominant phenotype (120, 121). Furthermore, exposure to dysbiotic signals can induce the upregulation of PD-L1 on tumor cells, delivering co-inhibitory signals that halt T-cell activation. In summary, dysbiosis cultivates a paradoxical “inflammatory-suppressive” microenvironment where chronic NF-κB-driven inflammation fuels mutagenesis, while the simultaneous activation of immune checkpoints and suppressive cytokines safeguards these aberrant cells from elimination, creating a sanctuary for HPV persistence and malignant progression (120–122). In summary, dysbiosis engenders not merely a singular inflammatory or suppressive response but rather cultivates a paradoxical yet harmonious pro-cancer microenvironment. Within this setting, chronic inflammation perpetually drives the malignant transformation of cells, while the concurrently robust immunosuppressive mechanisms safeguard these aberrant cells from detection and elimination by the immune system. This synergistic state of heightened inflammation and immunosuppression creates a sanctuary for the persistent infection of HPV and the advancement of precancerous lesions, forming the fundamental pathophysiological basis for the erosion of local immune surveillance.

Distinct from the systemic immunomodulatory influence of the gut microbiota, the local cervicovaginal microbiota exerts a direct and specific impact on the chemical composition of the reproductive tract microenvironment. In a healthy state, a resident Lactobacillus-dominated community maintains homeostasis through the production of beneficial metabolites, such as anti-inflammatory nucleotides (108, 110). However, the transition to precancerous lesions is characterized by a shift in this local ecosystem, where dysregulation of amino acid and nucleotide metabolism mirrors the interplay between a dysbiotic microbiome and host cellular hyperproliferation (110, 123). In the oncogenic stage, the intratumoral and vaginal microenvironments undergo significant lipid metabolic reprogramming (124, 125). This metabolic alteration enables cancer cells—synergistically supported by the altered local microbiome—to enhance de novo fatty acid synthesis, thereby securing the membrane components and signaling molecules required for rapid proliferation. Furthermore, local dysbiosis may sustain this oncogenic phenotype by creating a nutrient-rich biochemical niche that favors tumor cell survival (126, 127). Collectively, cervical carcinogenesis is driven by a complex, multifaceted cascade involving HPV infection, host cellular responses, and the vaginal microenvironment. As our comprehension of these dynamics deepens, clinical paradigms are evolving toward more precise, proactive methodologies. Elucidating the tripartite crosstalk among specific bacterial taxa, viral oncoproteins, and host signaling pathways is essential for uncovering the synergistic mechanisms of pathogenesis. In this context, next-generation risk assessment models are emerging that transcend traditional HPV genotyping. By integrating vaginal microbiome signatures with immune and metabolic biomarkers, these advanced systems aim to achieve multidimensional risk stratification. Such an integrated approach not only enhances the sensitivity of early screening but also informs individualized therapeutic strategies. Crucially, this conceptual evolution underpins the development of novel microbiome-based interventions. Modulating the cervicovaginal microenvironment—through probiotics, postbiotics, or targeted pharmacological agents to restore Lactobacillus dominance—offers a promising avenue to arrest the progression of precancerous lesions. This transition from passive screening to proactive microbiome-mediated interception represents a paradigm shift in the management of cervical cancer, offering a robust strategy for disease mitigation.

Dysbiosis exerts a profound influence on systemic pathophysiological alterations associated with the development of endometrial cancer through two primary mechanisms (35, 93). First, at the level of estrogen metabolism, specific bacterial taxa within the gut microbiota, notably Bacteroides and Clostridium, produce β-glucuronidase. This enzyme specifically hydrolyzes estrogen-glucuronide conjugates synthesized by hepatic enzymes UGT1A1 and UGT2B7. Such enzymatic action reactivates dormant estrogen, originally earmarked for biliary excretion, converting it back into its biologically active free form. These reactivated estrogen molecules subsequently enter the portal venous system via passive diffusion across the intestinal epithelial barrier, thereby completing the enterohepatic circulation and resulting in a significant augmentation of bioactive estrogen levels within the circulatory system (93, 132–134). Crucially, this unopposed hyperestrogenemia exerts a dual oncogenic effect: it directly stimulates abnormal endometrial cell proliferation while simultaneously signaling through immune receptors to dampen anti-tumor surveillance (135–137). Dysbiosis, alongside associated metabolic irregularities, can initiate systemic chronic inflammatory responses. In pathological states such as obesity, the integrity of the gut barrier is compromised, leading to augmented intestinal permeability. This compromised state permits substantial amounts of LPS—essential constituents of the cell walls of Gram-negative bacteria—to traverse into the circulatory system, consequently resulting in elevated plasma concentrations of LPS (70, 138, 139). These endotoxins bind to TLR4 and its downstream NF-κB signaling pathway, activating the mononuclear-macrophage system and leading to the release of a large number of pro-inflammatory cytokines, thereby establishing a state of systemic chronic low-grade inflammation. This persistent inflammatory microenvironment not only increases genomic instability by producing ROS but also promotes cell proliferation and angiogenesis, creating conditions conducive to tumor initiation and progression (129, 140–142).

In the pathogenesis of endometrial cancer, local dysbiosis of the vaginal and uterine microbiome constitutes a critical promoting factor. This stage is characterized by a structural imbalance in the reproductive tract microecology: protective Lactobacillus species are significantly depleted, while strictly anaerobic pathogenic bacteria such as Atopobium vaginae, Porphyromonas somerae, and Dialister microerophilus exhibit several-fold abnormal enrichment. These changes in microbial composition directly led to the collapse of the local defense system— the decrease in lactic acid concentration produced by Lactobacillus raises the vaginal pH from a physiological range of 3.8-4.2 to a pathological range of 4.5-6.0, disrupting the acidic environment that inhibits the growth of pathogenic bacteria (33, 62, 92, 143).Simultaneously, the expression levels of the antimicrobial peptide LL-37 and the concentration of IgA on the mucosal surface exhibited a marked reduction of approximately 60% and 45%, respectively. This substantial decline significantly undermined the local physical and immune barrier functions. In light of such a comprehensive weakening of defensive mechanisms, opportunistic pathogens within the vagina were afforded the opportunity for retrograde ascension, successfully breaching the cervical barrier and colonizing the uterine cavity. This process created the requisite microenvironmental conditions that could facilitate subsequent carcinogenic processes. A recent comprehensive narrative review by Aquino et al. has provided critical evidence reinforcing this pathological transition. By systematically comparing the microbiota status between patients affected by endometrial cancer and healthy controls, the authors highlighted that the deviation from eubiosis is distinct and quantifiable. They emphasized that affected patients exhibit a specific “microbial signature” characterized not only by the depletion of protective Lactobacillus species but also by a correlating shift in vaginal pH and inflammatory markers compared to healthy individuals. This “affected versus healthy” dichotomy suggests that specific dysbiotic patterns—such as the overgrowth of Atopobium and Porphyromonas—are not merely concurrent features but may serve as early indicators of the carcinogenic cascade. Integrating these findings confirms that monitoring the microbiota status offers a novel lens for distinguishing high-risk populations from healthy cohorts (144). Current researches have unequivocally established the pivotal role of the microbiota in the etiology of endometrial cancer. The microbiota not only influences cellular proliferation through the regulation of estrogen metabolism but also fosters genomic instability via the activation of inflammatory pathways. Moreover, it modifies the characteristics of the TME through its metabolic byproducts (54, 145, 146). These findings provide a novel biological foundation for elucidating health disparities across different racial groups and underscore the potential for developing innovative prevention and treatment strategies centered on microenvironmental regulation.

Pathogenic bacteria that colonize the uterine cavity play a pivotal role in the malignant transformation of endometrial cells through a complex array of molecular mechanisms. At the inflammatory activation level, Atopobium vaginae interacts with TLR 2 via its surface lipoproteins, initiating MyD88-dependent signaling pathways that facilitate the nuclear translocation of the NF-κB transcription factor. This process triggers a cascade of pro-inflammatory cytokines, including IL-6, IL-8, and TNF-α, thereby establishing a persistently inflammatory microenvironment (145, 147). In terms of epigenetic regulation, butyrate produced through the metabolism of Porphyromonas somerae exerts an inhibitory effect on HDACs. This results in conformational changes in chromatin that impact the transcriptional expression of genes associated with DNA damage repair. Furthermore, concerning genomic stability, ROS generated during microbial metabolism can inflict oxidative damage on DNA, significantly heightening the mutation burden of critical tumor suppressor genes such as PTEN (132, 148). Additionally, metalloproteases and other proteolytic enzymes secreted by pathogenic bacteria have the capacity to specifically degrade tight junction proteins, such as occludin and ZO-1. This degradation disrupts the integrity of the endometrial epithelial barrier, thereby perpetuating a vicious cycle of infection, inflammation, and tissue damage (149–151). Collectively, these synergistic molecular events establish the fundamental pathological and physiological framework through which microorganisms facilitate the development of endometrial cancer.

In summary, the occurrence and progression of endometrial cancer is a complex pathological and physiological process driven by the interplay of systemic endocrine disorders, local microenvironment disruptions, and dysbiosis of microbiota. The core factor is the sustained high levels of estrogen, which act as a classical driving force by activating estrogen receptor signaling pathways, providing the initial signal for the abnormal proliferation of endometrial cells. At the same time, microbiota dysbiosis originating from the vagina or intestine plays a crucial role as a multiplier and accelerator. The three mechanisms—hormonal drive, inflammatory damage, and direct microbial action—are interwoven, forming a powerful positive feedback loop that collectively promotes the transformation of endometrial tissue from a normal state through hyperplasia and atypical hyperplasia, ultimately accelerating the transition to a malignant phenotype. This new understanding, which spans from the systemic to the local and from the macro to the micro, not only provides a powerful new microbiological tool for the early screening and stratification of high-risk populations for endometrial cancer but also lays a solid theoretical foundation for future disease prevention and treatment through targeted regulation of the microecological environment, such as the application of probiotics.

Recent advancements have shifted the focus from isolated local dysbiosis to the concept of the gut–vaginal microbiome axis, a bidirectional communication network that critically influences ovarian cancer pathogenesis. This crosstalk suggests that the gut acts as an extra-vaginal reservoir for bacterial populations and modulates the vaginal microenvironment through metabolic and immune signaling, thereby impacting cancer susceptibility and progression. Genetic susceptibility, particularly BRCA1 and BRCA2 mutations, remains a cornerstone of ovarian cancer risk (4, 5). However, emerging evidence indicates that these genetic factors do not act in isolation but significantly shape the gut–vaginal microbial landscape (154, 155). A key case-control study revealed that BRCA1 mutation carriers, particularly those under 50, exhibit a distinct “Community State Type O” (CST-O), characterized by a marked depletion of protective Lactobacillus species in the cervicovaginal niche. Notably, this loss of local dominance is often mirrored by or linked to gut dysbiosis, where the “estrobolome”—gut bacteria capable of metabolizing estrogens—may alter systemic hormone levels, further disrupting vaginal homeostasis (23) This data suggests that the microbial microenvironment serves as a crucial mediator between genetic predisposition and tumorigenesis (Figure 4) (23, 156–158). The gut–vaginal crosstalk implies that dysbiosis in one compartment may trigger or sustain dysbiosis in the other, creating a systemic pro-tumorigenic environment. Consequently, simultaneous profiling of both gut and vaginal microbiomes could offer a more robust strategy for early risk stratification in BRCA carriers than analyzing either site alone.

Chronic infections caused by specific pathogens are considered one of the risk factors for ovarian cancer. The mechanisms involved include the induction of chronic inflammation and the disruption of normal cellular apoptosis processes, which can promote carcinogenesis. Several studies have confirmed a significant association between Chlamydia trachomatis infection and an increased risk of ovarian cancer. Serological tests have shown that positive antibodies against specific proteins of Chlamydia trachomatis (Pgp3) are associated with approximately a two-fold increase in risk of ovarian cancer (159–161). This association is specific, as antibodies against other common pathogens have not shown an association with risk of ovarian cancer (159, 160). The potential carcinogenic mechanism of Chlamydia trachomatis may be associated with its capacity to inhibit apoptosis in host cells. Research has indicated that Chlamydia trachomatis disrupts the functionality of the tumor suppressor protein p53, thereby obstructing the apoptotic process in infected cells. Under conditions of DNA damage, p53 is responsible for initiating repair mechanisms or triggering apoptosis to avert the development of cancer cells. By inhibiting the action of p53, Chlamydia trachomatis fosters an environment conducive to its own replication within host cells, while simultaneously permitting the survival of cells that harbor accumulated DNA damage. The paradigm raises the likelihood of these damaged cells ultimately progressing toward carcinogenesis (162). Chronic inflammation caused by infections, such as pelvic inflammatory disease (PID), is an important risk factor for the increased risk of ovarian cancer associated with chlamydia infection (161, 163, 164). In addition to Chlamydia trachomatis, other intracellular microorganisms that can cause chronic infections have also been found to be associated with ovarian cancer. Researchers have identified pathogens such as Brucella, Mycoplasma, and Chlamydia in ovarian cancer tumor cells (163, 165). A recent systematic review and meta-analysis highlighted evidence demonstrating a significantly higher prevalence of Chlamydia trachomatis DNA in ovarian cancer tissues than in benign ovarian tumors (166). While research into the relationship between these pathogens and ovarian cancer is still evolving, current evidence indicates that both the prevention and treatment of chronic infections caused by these pathogens could potentially mitigate the risk of ovarian cancer in certain women (164, 165). Therefore, integrating the detection of specific pathogens with an assessment of the broader gut–vaginal microbial network holds significant promise. This dual approach could not only elucidate the etiology of “infection-associated” ovarian cancers but also lead to novel early diagnostic panels that combine pathogen screening with microbiome signatures (Figure 4).

The tumor-associated microbiome emerges as a dynamic driver of oncogenesis rather than a passive bystander, actively dictating the immunological configuration of ovarian cancer. Ovarian cancer typically manifests as a non-immunogenic “cold” tumor, characterized by the exclusion of cytotoxic T cells and the dominance of immunosuppressive myeloid populations. Specific intratumoral pathogens actively enforce this immune-excluded state. Researches have highlighted that Acinetobacter species can drive the polarization of tumor-associated macrophages (TAMs) towards an immunosuppressive M2 phenotype. These M2-TAMs secrete TGF-β and IL-10, forming a dense stromal barrier that physically and chemically excludes CD8⁺ T cells from tumor islets, thereby maintaining an inflammatory state conducive to immune evasion (153, 167). Beyond direct immune suppression, intratumoral dysbiosis hijacks developmental signaling pathways to fuel progression. Notably, Cutibacterium acnes (formerly Propionibacterium acnes) has been identified as a pivotal promoter of malignancy. Mechanistically, inflammatory responses elicited by C. acnes trigger the aberrant activation of the Hedgehog (Hh) signaling pathway, elevating the expression of critical proteins including Shh, Gli1, and Gli2. This reactivation of dormant developmental pathways synergizes with chronic inflammation to accelerate cellular proliferation and invasion (167–169). Conversely, modulation of the microbiota offers a pathway to reverse this aggressive phenotype. Favorable commensal signals (e.g., STING agonists) can stimulate DCs to produce Type I Interferons, which upregulate T-cell-attracting chemokines (CXCL9, CXCL10). This establishes a chemokine gradient that facilitates the trafficking of effector T cells into the tumor core, transforming the “cold” immune desert into an immune-inflamed “hot” tumor. This microbial-driven immunological switch is increasingly recognized as a critical determinant of patient prognosis and therapeutic response (67, 170–172).

The microbial communities in the gut and local tumor environment significantly influence the effectiveness of first-line chemotherapy for ovarian cancer through various complex mechanisms. These microbial communities can not only directly induce drug resistance in cancer cells but also indirectly weaken the efficacy of chemotherapy by regulating systemic immunity and inflammatory responses.

LPS, a critical component of the cell wall of Escherichia coli (E. coli), has been identified as a significant contributor to chemotherapy resistance in cancer. Research indicates that TLR4, which is expressed on the surface of ovarian cancer cells, is capable of recognizing LPS. Upon binding of LPS to TLR4, the downstream MyD88 and NF-κB signaling pathways are activated. This activation triggers tumor cells to secrete a variety of pro-inflammatory cytokines and chemokines, thereby creating a microenvironment that is conducive to tumor growth. Notably, these factors also instigate anti-apoptotic mechanisms, enabling cancer cells to withstand apoptosis induced by chemotherapy agents such as paclitaxel, ultimately leading to resistance to such therapeutic interventions (173). Therefore, a pro-inflammatory microenvironment composed of specific microorganisms can directly weaken the effectiveness of chemotherapy by continuously activating inflammatory signals.

In addition to directly inducing resistance, the microbiome can also influence chemotherapy effectiveness through more macro-level regulation. During chemotherapy, this imbalanced immune state can interfere with the antitumor effects of chemotherapy drugs (174, 175). Clinical studies have found that ovarian cancer patients who are resistant to platinum-based chemotherapy exhibit significant differences in gut microbiota diversity and composition compared to those who are sensitive to platinum. The gut microbiota diversity is markedly reduced in resistant patients (176). The use of broad-spectrum antibiotics during chemotherapy significantly disrupts the gut microbiota, and this phenomenon is importantly associated with poorer treatment responses and survival rates in ovarian cancer patients. This further validates the critical role of a complete gut microbiome in maintaining chemotherapy sensitivity (177, 178).

Epithelial-mesenchymal transition (EMT) is a key biological process through which cancer cells acquire invasive and metastatic abilities as well as chemoresistance (179). Animal model studies have shown that dysbiosis of the gut microbiota may promote the occurrence of EMT. The mechanism behind this phenomenon may be closely related to the damage of the intestinal barrier function. Dysbiosis allows bacterial products, such as LPS, to enter the bloodstream, thereby activating peripheral immune cells, particularly macrophages. The activated macrophages then release a large number of pro-inflammatory factors, such as tumor TNF-α and interleukin-6, further exacerbating the inflammatory response (180). These inflammatory factors in the cycles act on tumor cells, inducing EMT, thereby enhancing their invasive capabilities and leading to resistance to chemotherapy drugs (153, 181).

The microbiota, whether present in the gut or locally within tumors, is a key factor in regulating host immune responses. Its composition and function profoundly affect the efficacy of anti-tumor therapies, including poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. PARP inhibitors are a cornerstone therapy for BRCA-mutated ovarian cancer. The efficacy is not only reliant on directly killing cancer cells with homologous recombination deficiency (HRD) through the synthetic lethality effect, but also partially depends on eliciting effective anti-tumor immune responses. The microbiome, as an important regulator of systemic and local immunity, can shape the TME, thereby indirectly influencing the effectiveness of PARP inhibitors. Research has shown that the composition of the gut microbiome is associated with the therapeutic effects of PARP inhibitors. In a study involving ovarian cancer patients treated with PARP inhibitors, a higher abundance of bacteria from the genus Phascolarctobacterium was significantly associated with longer progression-free survival (PFS) in BRCA wild-type patients (182). This indicates that the microbiome may exert an influence on patients’ responses to targeted therapy by modulating the immune system.

Chronic inflammation driven by persistent infections from certain pathogens or dysbiosis typically creates an immunosuppressive TME, thus weakening the efficacy of immunotherapy. Some intratumoral bacteria, have been found to be negatively correlated with the infiltration of M1 pro-inflammatory macrophages and can inhibit the migration of macrophages, which may lead to a diminished antitumor immune response. The chronic inflammatory state maintained by dysbiosis recruits a large number of MDSCs and M2 tumor-associated macrophages, which are key immunosuppressive components in the tumor immune microenvironment. The presence is detrimental to the optimal immune-activating effects of therapies like PARP inhibitors (183, 184). In stark contrast to pathogenic bacteria, certain strains of lactic acid bacteria have demonstrated the remarkable capability to bolster the host’s anti-tumor immune response. Notably, research indicates that Lactobacillus gallinarum can impede the differentiation of immune-suppressive Tregs within the TME through the modulation of tryptophan metabolism (185). Simultaneously enhance the functionality of cytotoxic CD8⁺ T cells, thereby significantly improving the efficacy of anti-PD-1 immunotherapy in animal models (84). The significant depletion of lactobacilli observed in ovarian cancer patients may indicate a weakening of local immune surveillance, which not only promotes tumor development but may also affect the efficacy of various anticancer therapies, including PARP inhibitors and immune checkpoint inhibitors.

Research has demonstrated a noteworthy alteration in the intestinal microbiota of cervical cancer patients, characterized by a significant increase in the relative abundance of genera such as Prevotella, Porphyromonas, and Dialister. Concurrently, there is an observable decline in the prevalence of genera including Bacteroides, Alistipes, and various members of the family Lachnospiraceae. These findings underscore the promising potential of the microbiome as a valuable tool for monitoring disease progression, offering novel insights into the early diagnosis and efficacy assessment of cervical cancer (186). This dysbiosis may create conditions for cancer cell escape by weakening the immune surveillance function of the host. Predictive models based on these specific microbial characteristics have shown high accuracy in the diagnosis of cervical cancer (187).

The occurrence of endometrial cancer is closely related to the host’s metabolism and hormonal environment, with the gut microbiota playing a central role in regulating these two systems. Therefore, an in-depth analysis of the composition of the microbiota not only aids in understanding the mechanisms behind this disease but also highlights its significant potential as a novel, non-invasive biomarker. Research findings clearly indicate that the presence of specific microbial communities is directly associated with the risk of endometrial cancer. For instance, elevated levels of bacteria from the genera Marvinbryantia, Ruminococcaceae UCG014, and Dorea have been detected in European populations, which may suggest a lower risk of the disease and thus can be considered protective biomarkers. In contrast, a significant increase in the abundance of Erysipelotrichaceae family may serve as risk warning biomarkers, indicating that individuals should enhance the screening and health management efforts (95, 188, 189). This microbiome-based risk assessment is more accurate and individualized than relying solely on clinical indicators.

Endometrial cancer is an estrogen-dependent tumor. Therefore, detecting the abundance of gut microbiota related to estrogen metabolism (risk-related genus Lachnospira and the family Bifidobacteriaceae) can indirectly reflect an individual’s estrogen recycling levels, thus assessing the potential stimulatory effects on the endometrium. Many identified protective bacteria (certain members of the family Ruminococcaceae) are key producers of SCFAs like butyrate. Butyrate has multiple benefits, including regulating blood sugar, anti-inflammatory effects, and inhibiting tumor cell proliferation. Therefore, the levels of these microbiota can serve as indicators of host metabolic health and immune homeostasis, with their reduction potentially signaling a systemic microenvironment conducive to cancer development (189). In summary, microbiome has potential as a biomarker for endometrial cancer that goes beyond simple risk association. It can stratify risk, reveal mechanisms, and guide interventions, providing a scientific basis for achieving unprecedented personalized and population-specific prevention.

Ovarian cancer presents a formidable challenge in the realm of gynecologic malignancies, characterized by a high mortality rate, the complexity of early diagnosis, and a propensity for developing drug resistance. In the ongoing quest for innovative diagnostic and therapeutic strategies, the gut microbiome has emerged as a promising and non-invasive biomarker, distinguished by its myriad advantages. Recent studies have illuminated the unique structural characteristics of the microbiome in ovarian cancer patients, which starkly contrast with those observed in healthy individuals. Notably, there is a discernible increase in the abundance of specific bacterial taxa, such as Bacteroides, Prevotella, and Proteobacteria, while beneficial microorganisms, including Ruminococcus and Actinobacteria, exhibit a significant decline. This distinctive pattern of microbial dysbiosis functions akin to a microbial fingerprint, offering exciting potential for the development of a non-invasive screening tool aimed at identifying high-risk populations (190).

Individual differences in response to chemotherapy and immunotherapy play a pivotal role in treatment failure and recurrence in ovarian cancer. Platinum-based drugs remain the cornerstone of chemotherapy for this malignancy; however, the emergence of resistance presents a significant challenge. Extensive research has elucidated that the composition of the gut microbiota can profoundly influence the efficacy of platinum-based chemotherapy. Notably, the administration of antibiotics may severely disrupt the delicate balance of the microbiota, potentially leading to accelerated tumor growth and diminished sensitivity to chemotherapy (175, 176, 178). Thus, detecting the gut microbiota of patients before chemotherapy can help assess its potential as a biomarker and predict sensitivity to platinum-based drugs, thereby optimizing treatment regimens. Although immune checkpoint inhibitors (ICIs) have brought hope, their efficacy still needs improvement, and the gut microbiota influences the effectiveness of immunotherapy by modulating the immune system; specific bacteria may serve as biomarkers to predict responders. The dynamic changes in the gut microbiota are closely related to patients’ long-term survival and recurrence risk. A pro-cancer microbiota environment may accelerate tumor growth and result in poorer treatment responses, indicating a worse prognosis. Therefore, specific gut microbiota could serve as independent prognostic factors for assessing long-term survival rates and recurrence risks. Monitoring changes in the fecal microbiota of patients before and after treatment, as well as during recovery, can provide dynamic observations of potential recurrence and resistance. In summary, the gut microbiota plays a crucial role in the occurrence and treatment of ovarian cancer, with the potential to become a multidimensional biomarker, promoting the advancement of diagnosis and treatment towards precision and personalization.

Despite the transformative potential of microbial biomarkers in reshaping the diagnostic landscape of gynecological malignancies, the translation of these findings from bench to bedside is currently impeded by a “reproducibility crisis.” This challenge stems not from a lack of association, but from the intrinsic complexity and high inter-individual variability of the human microbiota. The composition of the gut and cervicovaginal ecosystems is not a static trait but a dynamic entity, continuously sculpted by a myriad of confounding factors including host genetics, ethnicity, dietary habits, antibiotic usage, and geographic location. Recent large-scale meta-analyses have highlighted that geographic origin often explains a greater proportion of microbial variance than the disease state itself. A pertinent example is provided by a recent Mendelian randomization study on endometrial cancer, which revealed distinct causal associations between specific gut taxa and cancer risk in European populations compared to East Asian populations (189). This underscores a critical limitation: a microbial biosignature identified in a specific demographic cohort may lack the necessary diagnostic sensitivity or specificity when extrapolated to a global population with divergent genetic and environmental backgrounds. A fundamental conceptual hurdle in overcoming this heterogeneity lies in the phenomenon of functional redundancy. In complex microbial communities, distinct bacterial taxa often possess homologous gene clusters capable of performing identical metabolic functions. Consequently, taxonomic variation does not always equate to functional alteration (13, 58). Relying solely on 16S rRNA gene sequencing—which provides a taxonomic census but lacks functional resolution—may obscure the true pathological mechanism. For instance, while the specific bacterial species constituting the “estrobolome” may vary significantly between individuals, the net enzymatic activity of β-glucuronidase—which drives estrogen reabsorption and promotes hormone-dependent tumorigenesis—might be the conserved oncogenic driver (33, 36, 132). Thus, the search for universal biomarkers must shift from identifying specific “bacterial names” to detecting conserved functional signatures, such as the enrichment of genes involved in inflammation-inducing LPS biosynthesis or tumor-promoting secondary bile acid metabolism (123, 127). To bridge the chasm between discovery and clinical application, future research paradigms must evolve toward multi-omics integration and systems biology. Emerging investigations in cervical cancer have demonstrated the efficacy of combining metagenomics with metabolomics to reconstruct the “microbe-host interactome.” By correlating microbial gene abundance with the levels of key metabolites—such as nucleotides, amino acids, and lipids—researchers can filter out taxonomic noise and pinpoint the actual metabolic dysfunctions fueling the transition from precancerous lesions to invasive carcinoma (123, 124, 127). Furthermore, integrating host proteomics allows for the assessment of how these microbial metabolic signals are transduced into host immune responses, providing a holistic view of the pathogenic landscape. Finally, to resolve the “chicken-or-egg” causality dilemma—determining whether dysbiosis is a driver of malignancy or a consequence of the TME—robust longitudinal cohort studies are indispensable. Future initiatives must prioritize large-scale, multi-center collaborations utilizing standardized sampling and sequencing protocols to minimize technical batch effects. Coupled with advanced machine learning algorithms capable of integrating high-dimensional microbiome data with clinical metadata, these rigorous approaches are essential for establishing a precise, reproducible, and universally applicable risk stratification system for gynecological cancers.