The oral cavity harbors a diverse microbial community, some members of which have been associated with oncogenic processes. Epidemiological studies have reported consistent associations between periodontal disease and increased pancreatic cancer risk (27,28), and prospective cohort analyses have identified specific oral taxa, particularly members of the ‘red’ and ‘orange’ complexes, as being linked to disease development (28). These microorganisms may disseminate to pancreatic tissue via hematogenous or lymphatic routes, and are hypothesized to contribute to pro-tumorigenic microenvironments through virulence-associated mechanisms (27,29). Porphyromonas gingivalis has been frequently implicated in this context; its gingipains have been shown to regulate MMP-9 expression through NF-κB signaling, which may influence extracellular matrix remodeling and tumor invasion (30,31). In addition, the production of nucleoside diphosphate kinase enables hydrolysis of extracellular ATP and inhibition of P2X7-mediated apoptosis, a mechanism that may permit the persistence of damaged cells (32). Following cellular invasion, P. gingivalis has been reported to modulate ERK1/2-Ets1, p38/HSP27, JAK/STAT and AKT signaling pathways, which may collectively contribute to enhanced cell survival under oncogenic conditions (27,33,34). Aggregatibacter actinomycetemcomitans produces cytolethal distending toxin, the CdtB subunit of which exhibits phosphatase activity that alters PIP3 signaling and may enhance PI3K pathway activation (35–38). Given the central role of PI3K in KRAS signaling, this mechanism may be relevant to early tumorigenesis (39–41).

The intrapancreatic microbiome is increasingly considered a distinct, low-biomass ecosystem that may become altered and metabolically active during PDAC progression (42). Although previously considered sterile, the pancreas has been shown to harbor microbial communities predominantly composed of Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria (24,43). The fungal component of the microbiome has also been implicated, with PDAC tissues exhibiting substantially increased fungal burden and distinct composition compared with normal pancreas (44). Malassezia species have been associated with activation of the mannose-binding lectin-complement pathway, whereby fungal glycans may induce C3 cleavage and C3a-mediated signaling, potentially promoting tumor cell proliferation and survival (44).

The gastrointestinal microbiome is increasingly recognized as a potential contributor to pancreatic cancer initiation through the gut-pancreas axis (45). Studies using metagenomic profiling have identified distinct gut microbial features in patients with PDAC, including reduced α diversity and shifts in phylum-level composition, such as increased Bacteroides and decreased Proteobacteria (46,47). These changes have been associated with increased levels of pro-inflammatory cytokines, including TNF-α, and may contribute to the establishment of a microenvironment permissive to tumor development (24,48). Chronic pancreatitis, a well-established risk factor for pancreatic cancer, has also been associated with gut microbiota dysbiosis, with reduced abundance of Enterococcus faecalis and other commensals suggesting a potential role for decreased microbial diversity in disease progression (49). In addition, small intestinal bacterial overgrowth may induce lipopolysaccharide-mediated inflammation and has been proposed to contribute to KRAS activation, particularly in the context of sustained inflammatory signaling (50).

Alterations in microbial metabolism may provide an additional mechanistic link between dysbiosis and pancreatic carcinogenesis. Reduced levels of commensal taxa such as Faecalibacterium and Akkermansia have been associated with disruptions in bile acid and tryptophan metabolic pathways, which may activate pro-inflammatory signaling and promote epithelial-mesenchymal transition (EMT) (51,52). Secondary bile acids may act as damage-associated molecular patterns, inducing reactive oxygen species (ROS) production and NF-κB activation, while microbial metabolism of tryptophan yields kynurenine derivatives that activate the aryl hydrocarbon receptor, promoting regulatory T-cell differentiation and suppressing antitumor immunity, thereby establishing an immunosuppressive environment conducive to tumor initiation (53). Helicobacter pylori has also been implicated in this context; chronic infection has been associated with alterations in gastric endocrine function, including reduced somatostatin secretion and increased secretin activity, which may contribute to pancreatic ductal hyperplasia (54). In addition, H. pylori overgrowth may promote N-nitrosamine formation and DNA damage, while the CagE protein has been reported to exhibit helicase activity and regulate DNA methylation, suggesting a potential role in mutagenesis (27). Together, these findings suggest that the gut microbiome may contribute to pancreatic cancer initiation through interconnected metabolic and immune mechanisms.

Accumulating evidence has indicated that tumor-promoting microbiota facilitate pancreatic cancer progression through convergent oncogenic mechanisms, despite taxonomic diversity (15,16). Fusobacterium nucleatum represents a prototypical example, integrating inflammatory signaling, extracellular matrix remodeling and immune evasion (57). Through Fap2-mediated adhesion, it induces pro-tumorigenic cytokine (IL-8 and CXCL1) secretion (58), while activation of p38 MAPK signaling enhances MMP-dependent matrix degradation (47). In parallel, F. nucleatum suppresses antitumor immunity via TIGIT engagement and promotes metastatic communication through extracellular vesicles, collectively driving aggressive disease phenotypes (59).

A second mechanistic axis involves protease-driven signaling and cytoskeletal remodeling, exemplified by P. gingivalis. Notably, gingipains from P. gingivalis activate protease-activated receptor (PAR)2 and downstream NF-κB signaling while simultaneously enhancing p38 pathway activity, leading to increased MMP activation and invasion (60). Moreover, P. gingivalis modulates cytoskeletal dynamics via protein citrullination, facilitating tumor cell motility (47,61). Other bacteria, including Klebsiella species and E. faecalis, reinforce these processes by sustaining chronic inflammation, inducing DNA damage, activating inflammasomes and promoting immune escape, thereby amplifying tumor progression (45,62,63).

In addition to signaling and inflammatory pathways, microbial regulation of tumor metabolism and the microenvironment has emerged as a critical determinant of disease progression. Pseudomonas species are implicated in amino acid metabolism and the induction of autophagy, potentially linking microbial activity to PI3K/AKT/mTOR signaling and tumor progression (64). Streptococcus anginosus further contributes through MAPK activation and proliferative signaling (65). P. gingivalis accelerates pancreatic cancer progression by fostering a neutrophil-dominated proinflammatory TME through enhanced secretion of neutrophilic chemokines (e.g., Cxcl1, Cxcl2, Cxcr2) and neutrophil elastase (66). These findings suggest that distinct microbial taxa converge on shared oncogenic programs, underscoring the microbiome as an integral regulator of pancreatic cancer progression.

In contrast to tumor-promoting microbiota, tumor-suppressive microbial species exert protective effects through convergent mechanisms centered on immune activation, metabolic regulation and maintenance of host-microbe homeostasis (67–69). Lactobacillus species, particularly Lactobacillus reuteri, exemplify this paradigm by enhancing antitumor immunity. Through promoting natural killer (NK)-cell recruitment and activation, as well as inducing M1 macrophage polarization via inhibition of Toll-like receptor (TLR)4 signaling, Lactobacillus strengthens innate immune responses within the TME (56,70). Additionally, microbial metabolites such as acetate further potentiate T-cell and NK-cell function, reinforcing systemic and local antitumor immunity (70).

Another key protective microbe, Akkermansia muciniphila, contributes to pancreatic cancer suppression through modulation of host immunity and preservation of mucosal barrier integrity (71). This mucin-degrading bacterium is enriched in long-term survivors with pancreatic cancer and is associated with a T cell-inflamed TME (72). A. muciniphila enhances antitumor immunity by promoting M1-like macrophage polarization, activating the NLRP3 inflammasome and increasing T-cell infiltration into tumors (73). Notably, in patient-based studies, restoration of A. muciniphila has been associated with improved responses to chemotherapy (71,74). However, its effects appear to be context-dependent, as excessive colonization may compromise barrier function and induce systemic inflammation (75).

Metabolic regulation constitutes an additional layer of tumor suppression. Faecalibacterium prausnitzii and Bifidobacterium species, both reduced in PDAC, produce short-chain fatty acids (SCFAs) such as butyrate that inhibit tumor proliferation, induce apoptosis and enhance immune activation (76–78). Loss of these beneficial microbes leads to impaired barrier function, reduced SCFA production and increased susceptibility to pro-tumorigenic inflammation (78). Collectively, these findings illustrate that tumor-suppressive microbiota converge on key host pathways to counteract pancreatic cancer progression, providing a conceptual framework for microbiome-based therapeutic strategies.

The oral-gut-tumor microbial axis may shape PDAC progression through coordinated effects on adaptive immunity, myeloid-cell function, innate sensing pathways and metabolite-mediated immune regulation. Emerging evidence has suggested that gut microbiome dysbiosis contributes to T-cell exclusion and dysfunction, whereas microbiota depletion is associated with enhanced intratumoral T-cell infiltration, reduced myeloid-derived suppressor cell (MDSC) accumulation and suppression of tumor growth in preclinical models (22,79). IL-17 appears to represent an important mechanistic link, as IL-17 neutralization abrogates the tumor-suppressive effect of antibiotic treatment, suggesting a connection between commensal-driven T helper 17 (Th17) responses and PDAC immune evasion (80,81). In parallel, PDAC-derived CCL2 recruits monocytic MDSCs and promotes acquisition of a suppressive phenotype characterized by increased ROS and arginase production, a process that may be partially dependent on MAPK signaling (82).

Microbial regulation of the PDAC immune landscape also involves tumor-intrinsic immunosuppressive programs, innate immune sensing pathways and metabolite-dependent signaling. Thrombin-PAR1 signaling has been linked to reduced cytotoxic T-cell infiltration and increased tumor-associated macrophage accumulation through upregulation of Csf2 and Ptgs2 (83). In addition, microbial products (e.g., lipopolysaccharides, flagellins) engage TLRs, cGAS-STING and NOD-like receptors, generating context-dependent effects that range from chronic tumor-promoting inflammation to type I interferon-mediated antitumor responses (22,80,84). Microbial metabolites, including SCFAs, secondary bile acids and tryptophan catabolites, may regulate inflammasome activity, chromatin accessibility, NK-cell function and T-cell differentiation (80,85–87). Furthermore, disruption of gut barrier integrity may facilitate systemic endotoxemia, promoting myeloid skewing and stromal remodeling (88).

Collectively, these observations suggest that microbiota-mediated immune regulation converges on several key pathways, including IL-17/Th17 signaling, CCL2-dependent MDSC recruitment and PAR1-associated myeloid programming. These findings raise the possibility that targeted modulation of microbial communities or their metabolites could help reprogram the PDAC TME toward more durable antitumor immunity.

Obesity and type 2 diabetes mellitus (T2DM) are consistently associated with an elevated risk of PDAC and adverse outcomes (8). Pancreatic cancer and T2DM exhibit a bidirectional relationship, in which diabetes acts as both a risk factor and a metabolic consequence of occult pancreatic malignancy (89,90). In available epidemiological analyses, T2DM has been associated with an increased annual incidence rate of PDAC, with a standardized incidence ratio of 1.54 (95% CI, 1.45–1.64) (91). Major contributors to this association include hyperglycemia, hyperinsulinemia, pancreatitis, dyslipidemia, insulin resistance and inflammatory processes within the TME (92). Obesity may further amplify this axis by increasing circulating insulin levels, and altering leptin and adiponectin signaling (93–95).

Obesity and diabetes promote pancreatic carcinogenesis through a convergent immunometabolic program (96). Excess nutrient availability and metabolite accumulation support carcinogenesis by amplifying mutagenic and genotoxic stress, while obesity- and diabetes-associated alterations in gastrointestinal and sex-hormone signaling interact with microbiome dysfunction to foster an immunosuppressive TME (96,97). Adipokines regulate metabolic homeostasis, inflammatory cascades and immune surveillance through direct effects on the TME. Among these mediators, adiponectin is generally considered tumor-suppressive, whereas leptin promotes proliferative, angiogenic and pro-inflammatory signaling (98). The net effect of adipokine dysregulation in obesity therefore shifts the tumor ecology toward a PDAC-permissive state (98). These changes are reinforced by autophagy dysregulation, endoplasmic reticulum stress, oxidative stress, EMT and exosome secretion, all of which contribute to malignant transformation and tumor evolution (99–102). These observations support earlier pancreatic cancer screening in selected high-risk individuals, particularly those with new-onset diabetes or unexplained metabolic deterioration.

The so-called obesity paradox has attracted growing interest in cancer immunotherapy. Although obesity is generally associated with an increased risk of PDAC and a chronic pro-inflammatory state (8), several clinical studies have reported comparable or, in some settings, improved responses to immune checkpoint inhibitors among obese patients (103,104). While the clinical relevance of this phenomenon remains incompletely understood, emerging evidence has suggested that obesity-associated alterations in the gut microbiome may interact with systemic and intratumoral immune pathways through multiple interconnected mechanisms. At the metabolic level, gut microbiota-derived SCFAs regulate colonic macrophage function and Treg cell homeostasis, while influencing host leptin secretion, a hormone that correlates with PD-1 expression on CD8⁺ T cells and promotes pro-inflammatory macrophage polarization through TNF-α and IL-6 production (105). Immunologically, specific commensal bacteria such as Bacteroides fragilis modulate the balance between CD4⁺ T cell subsets by mediating regulatory T cell conversion, whereas Lactobacillus species translocate to secondary lymphoid organs to influence Th1/Th17 responses (105). Notably, Bifidobacterium can stimulate antitumor immunity via T cell cross-reactivity between bacterial surface epitopes and tumor neoantigens (105). These microbiota-mediated immune modulations collectively shape the tumor microenvironment, which is characterized in obese patients by increased infiltration of exhausted CD8⁺ T cells with elevated PD-1 expression, enhanced natural killer cell activity and a pro-inflammatory M1-like macrophage phenotype, features that may underlie the improved therapeutic responses to immune checkpoint inhibitors observed in this patient population (105).

Evidence from diet-induced mice obesity models indicates that CD8⁺ tumor-infiltrating lymphocytes exhibit impaired effector function, characterized by reduced expression levels of Ifng, Prf1 and Gzmb, together with a metabolic shift from glycolysis toward oxidative phosphorylation. Notably, this dysfunctional state is not accompanied by increased expression of canonical exhaustion markers (106). Diet-induced weight loss, but not semaglutide-induced pharmacological weight normalization, has been shown to restore T-cell effector function and improve responses to immunotherapy (106). These findings suggest that metabolic health, rather than body mass index alone, may influence antitumor immune competence and treatment efficacy. They are also consistent with the possibility that obesity-associated microbial and inflammatory states contribute to shaping immune fitness and drug responsiveness.

Although some studies have reported an association between obesity and improved survival in patients with pancreatic cancer, the obesity paradox in PDAC should currently be viewed as a hypothesis-generating concept rather than an established clinical paradigm (107). Several non-mutually exclusive mechanisms may contribute to the observed heterogeneity, including differences in body composition (visceral adiposity vs. sarcopenia), metabolically healthy vs. unhealthy obesity phenotypes, treatment dose normalization and obesity-associated microbiome configurations that may influence immune priming (105,106). Future prospective studies incorporating metabolic, body-composition and microbiome-based stratification may help clarify causality, and facilitate the development of personalized immunotherapy strategies and microbiome-targeted co-interventions.