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Esophageal Squamous Cell Carcinoma / Intratumor Bacteria / Cell Line, Tumor · Journal article
Gut Microbes · June 11, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a mechanistic study that profiled intratumoral microbiota in 27 ESCC patients and identified Lactobacillus reuteri-derived D-lactate as a driver of ferroptosis resistance through STAT3 K631 lactylation. Findings are supported by cell line and xenograft experiments using genetic perturbation, but lack clinical efficacy endpoints or human therapeutic evidence.
Observational microbiota profiling with integrated mechanistic studies in cell lines and mouse xenografts. 27 patients with esophageal squamous cell carcinoma; setting not specified. ESCC cell lines and nude-mouse xenografts used for mechanistic studies.. Intervention: L. reuteri exposure; D-lactate; STAT3 lactylation at K631. Compared with: ldhD-deficient L. reuteri mutant; STAT3 K631R; wild-type STAT3. China (Shanghai and Nanjing institutions).
16S rRNA sequencing of 102 multiregional tissue blocks from 27 ESCC patients identified Lactobacillus, particularly L. reuteri, as a tumor-enriched taxon associated with adverse survival L. reuteri-derived D-lactate induced site-specific STAT3 lactylation at lysine 631, promoting STAT3 dimerization and nuclear translocation D-lactate upregulated ferroptosis suppressors GPX4 and FTH1, reducing ferroptotic vulnerability and enhancing ESCC growth in cell lines and xenografts
Study does not report effect sizes (e.g., fold-change, hazard ratio) for adverse survival association 16S rRNA sequencing of 102 multiregional tissue blocks from 27 ESCC patients identified Lactobacillus, particularly L. reuteri, as a tumor-enriched taxon associated with adverse survival
These findings suggest a novel mechanism by which intratumoral Lactobacillus promotes ferroptosis resistance in ESCC, with potential implications for understanding probiotic supplementation effects in this cancer type. However, no clinical efficacy data are provided, and translation to human therapy remains speculative.
Mechanistic study in cell lines and mouse xenografts identifying a bacterial metabolite–host signaling axis in ESCC, but lacks clinical efficacy data and human therapeutic validation.
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These findings suggest a novel mechanism by which intratumoral Lactobacillus promotes ferroptosis resistance in ESCC, with potential implications for understanding probiotic supplementation effects in this cancer type. However, no clinical efficacy data are provided, and translation to human therapy remains speculative.
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Tumor-resident microbiota are increasingly recognized as active components of the gastrointestinal tumor ecosystem, yet how intratumor bacteria reshape cancer cell stress responses in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, 16S rRNA gene sequencing of 102 multiregional tissue blocks from 27 patients with ESCC, integrated with untargeted metabolomics, RNA sequencing, and mass spectrometry, identified Lactobacillus, particularly Lactobacillus reuteri, as a tumor-enriched taxon associated with adverse survival. Mechanistic studies in ESCC cell lines and nude-mouse xenografts revealed a distinctive dynamic: in contrast to host-derived L-lactate, L. reuteri-derived D-lactate induced site-specific STAT3 lactylation at lysine 631, thereby promoting STAT3 dimerization and nuclear translocation. This host signaling rewiring upregulated the ferroptosis suppressors GPX4 and FTH1, reduced ferroptotic vulnerability, and enhanced ESCC growth. Disrupting bacterial D-lactate production using a ldhD-deficient L. reuteri mutant or blocking host STAT3 lactylation using STAT3-knockout cells reconstituted with wild-type STAT3 or lactylation-defective STAT3 K631R, abolished the pro-tumor and antiferroptotic effects in vitro and in vivo. Together, these findings define a tumor-resident microbe-metabolite-host signaling axis that links intratumor Lactobacillus to ferroptosis escape. By establishing bacteria-derived D-lactate as the functional driver, the study provides a novel mechanistic framework that extends beyond the classical Warburg effect for developing biomarkers and therapeutic strategies targeting STAT3 lactylation or ferroptosis sensitization. These translatable results emphasize the need for context-specific evaluation of Lactobacillus-containing probiotic supplementation in patients with ESCC.
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