Senescence frequently occurs in cancer cells in response to chemotherapy (called therapy-induced senescence). Senescent cells can exert paracrine effects through the senescence-associated secretory phenotype (SASP) promoting cancer recurrence and chemoresistance. The altered gut microbiota has been closely associated with cancer progression through the direct interaction with cancer cells. However, little is known about the relationship between the gut microbiota and therapy-induced senescent cells. This study aimed to explore the impact of the gut microbiota on therapy-induced senescent cells and the SASP. We found that esophageal squamous cell carcinoma (ESCC) cells were induced into senescence following platinum-based chemotherapy, accompanied by the secretion of a robust SASP. Furthermore, senescent ESCC cells exerted a tumor-promoting effect through the SASP both in vitro and in vivo. Through 16S rRNA gene sequencing and fluorescence in situ hybridization, we identified that Fusobacterium nucleatum (F. nucleatum) was abundant in human ESCC cancerous tissues and correlated with poor prognosis in ESCC patients. Notably, F. nucleatum further promoted the secretion of the SASP by senescent ESCC cells. Compared with the conditioned medium from senescent ESCC cells, the conditioned medium from F. nucleatum-treated senescent ESCC cells accelerated tumor growth in xenograft models, enhanced migration and invasion abilities, and potentiated chemoresistance both in vitro and in vivo. Mechanistically, F. nucleatum invaded and survived in senescent ESCC cells and induced an increase in DNA damage to further activate the DNA damage response pathway, thus enhancing the SASP. Altogether, these findings reveal for the first time that F. nucleatum promotes the secretion of chemotherapy-induced SASP to drive ESCC progression and chemoresistance, which supports F. nucleatum as a potential target for ESCC therapy.

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