Gut microbiota-derived indole-3-lactic acid suppresses anti-PD-1 efficacy in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy where the efficacy of anti-PD-1 immunotherapy varies among individuals, possibly influenced by the gut microbiota. Here, we analyze 122 fecal samples from ESCC patients undergoing neoadjuvant immunotherapy and identify an enrichment of Ligilactobacillus salivarius (L. salivarius) in non-responders. Humanized microbiome, orthotopic ESCC mouse models, and single-cell RNA sequencing confirm that L. salivarius-produced indole-3-lactic acid (ILA) suppresses tumor-infiltrating NKG7⁺CD8⁺ Tpex cells, impairing anti-tumor immunity. Moreover, ILA-deficient L. salivarius strains abolish ILA production and immune resistance. In vitro assays reveal that ILA targets the aryl hydrocarbon receptor and downregulates nuclear factor κB (NF-κB) signaling in Tpex cells. Pharmacological NF-κB activation restores Tpex function and reverses resistance. Two validation cohorts support the L. salivarius-ILA-NKG7⁺CD8⁺ Tpex axis as a resistance mechanism in ESCC patients. These findings highlight L. salivarius and ILA as key modulators of the tumor microenvironment, offering potential strategies for overcoming immunotherapy resistance in ESCC.