Role of the oral-gut microbiota axis in pancreatic cancer: a new perspective on tumor pathophysiology, diagnosis, and treatment

Abstract

Pancreatic cancer, one of the most lethal malignancies, remains challenging due to late diagnosis, aggressive progression, and therapeutic resistance. Recent advances have revealed the presence of intratumoral microbiota, predominantly originating from the oral and gut microbiomes, which play pivotal roles in pancreatic cancer pathogenesis. The dynamic interplay between oral and gut microbial communities, termed the "oral-gut microbiota axis," contributes multifacetedly to pancreatic ductal adenocarcinoma (PDAC). Microbial translocation via anatomical or circulatory routes establishes tumor-resident microbiota, driving oncogenesis through metabolic reprogramming, immune regulation, inhibition of apoptosis, chronic inflammation, and dysregulation of the cell cycle. Additionally, intratumoral microbiota promote chemoresistance and immune evasion, further complicating treatment outcomes. Emerging evidence highlights microbial signatures in saliva and fecal samples as promising non-invasive diagnostic biomarkers, while microbial diversity correlates with prognosis. Therapeutic strategies targeting this axis-such as antibiotics, probiotics, and engineered bacteria-demonstrate potential to enhance treatment efficacy. By integrating mechanisms of microbial influence on tumor biology, drug resistance, and therapeutic applications, the oral-gut microbiota axis emerges as a critical regulator of PDAC, offering novel perspectives for early detection, prognostic assessment, and microbiome-based therapeutic interventions.

Keywords: Early diagnosis; Immune regulation; Oral-gut microbiota axis; Pancreatic cancer; Theraputic application.

Fig. 1

The intratumour microbiome-immune-PDAC axis. Intratumoral fungi (such as Malassezia or Chaetomium) and their acellular extracts promote the secretion of interleukin (IL)-33 through the dectin-1 receptor-mediated Src-Syk-CARD 9 pathway. The secretion of IL-33 enriches helper T cells 2, group 2 innate lymphoid cells, and T lymphocytes in the tumor microenvironment (TME), thereby promoting the progression of pancreatic ductal adenocarcinoma (PDAC). Additionally, intratumoral fungi can activate the complement cascade of complement 3 (C3) via the “lectin pathway,” leading to the breakdown of C3 into C3a and C3b. C3a promotes the proliferation of PDAC cells by binding to C3a receptors on cancer cell surfaces. Intratumoral bacteria inhibit TAM 1 polarization by activating toll-like receptors (TLRs) on cell surfaces, accompanied by an increase in TAM 2 transformation, ultimately facilitating tumor cell proliferation and tumor angiogenesis. They also promote the secretion of IL-1β through TLR 4 and NLR on PDAC cell surfaces via NF-κB and CASP-1, respectively. The secretion of IL-1β indirectly promotes TAM 2 activation by activating pancreatic stellate cells. Intratumoral bacteria also promote the secretion of neutrophil chemokines in the TME of PDAC, leading to the enrichment of tumor-associated neutrophils 2 (TAN 2) in the TME. Finally, the high diversity of the intratumoral microbiome enhances the activity of CD 8 ⁺ T cells to suppress PDAC

Fig. 2

The mechanism by which Porphyromonas gingivalis inhibits apoptosis. P. gingivalis interferes with the signaling of the Jak 1/Akt/Stat 3 pathway, suppressing the activity of the pro-apoptotic protein Bad on the mitochondrial membrane and increasing the ratio of Bcl-2 (anti-apoptotic) to Bax (pro-apoptotic). As a result, there are abnormal mitochondrial membrane permeabilities, leading to a reduced release of Cyt C, the “core” of mitochondrial-mediated apoptosis, which ultimately blocks the activation of downstream Caspase-9 and the executor of apoptosis, Caspase-3. Furthermore, P.gingivalis can upregulate the expression of miR-203, thereby inhibiting the important factor SOCS3 in the Jak 1/Akt/Stat 3 pathway, contributing to the suppression of apoptosis. Lastly, P.gingivalis can secrete nucleoside diphosphate kinase (NDK) to prevent apoptosis mediated by the purinergic receptor P2 × 7