Core Viewpoint - The study reveals that the gut microbiota, specifically Lactobacillus salivarius, induces resistance to anti-PD-1 therapy in esophageal squamous cell carcinoma (ESCC) through its metabolite indole-3-lactic acid (ILA), providing potential new strategies to overcome this resistance [2][4][6]. Group 1 - The research team analyzed 122 fecal samples from ESCC patients undergoing neoadjuvant immunotherapy, finding significant enrichment of Lactobacillus salivarius in non-responders [3]. - ILA produced by Lactobacillus salivarius inhibits tumor-infiltrating NKG7⁺ CD8⁺ Tpex cells, promoting their terminal exhaustion and weakening anti-tumor immunity [3][4]. - ILA targets the aryl hydrocarbon receptor (AhR) and downregulates the NF-κB signaling pathway in Tpex cells, with pharmacological activation of NF-κB restoring Tpex cell function and reversing immunotherapy resistance [3][4]. Group 2 - The findings indicate that Lactobacillus salivarius and its derived ILA are key regulatory factors in the tumor microenvironment (TME), offering potential strategies to overcome immunotherapy resistance in ESCC [6].