Curcumin blocks Fusobacterium nucleatum-driven tumor progression and carcinogenesis in ESCC via inhibiting the TLR4/MYD88/TRIF/STAT3 axis.

Abstract

Background: The molecular mechanisms by which the epidemiologically linked bacterium Fusobacterium nucleatum (Fn) promotes Esophageal Squamous Cell Carcinoma (ESCC) malignancy are poorly defined. Here, we identify the key signaling pathways involved.

Methods: We first established the intratumoral microbiota profile to focus on Fn's role in ESCC. Using integrated models, we then confirmed that Fn promotes tumor growth, which a cisplatin (CDDP)-induced senescence model also showed contributes to chemoresistance. Finally, by analyzing key signaling molecules, we elucidated the mechanisms by which Fn drives proliferation and treatment resistance.

Results: We began by observing a positive correlation between Fn enrichment and elevated TLR4/STAT3 signaling in ESCC patients. Subsequent experiments in cells and animals confirmed that this correlation functionally contributes to increased tumor aggressiveness. At the mechanistic level, Fn-derived lipopolysaccharide (LPS) acts as the key trigger, activating the TLR4/MYD88/TRIF/STAT3 axis to drive pro-inflammatory signaling and SASP, thereby leading to chemoresistance. Therapeutically, curcumin counters this by directly inhibiting Fn and blocking the pathway, thereby suppressing tumor growth, attenuating SASP, and restoring drug sensitivity.

Conclusion: The inhibition of the Fn-activated TLR4/MYD88/TRIF/STAT3 cascade represents a key mechanism through which curcumin blocks ESCC progression, identifying it as a promising candidate for therapeutic development.