Blood Microbiome Reveals the Impact of Lactobacillus on the Efficacy of Immunotherapy in Gastrointestinal Cancer

Abstract Immunotherapy has revolutionized the treatment of gastrointestinal (GI) cancers, but reliable biomarkers for predicting treatment efficacy remain limited. In this study, we explored the potential of blood microbiome and specific microbial taxa as novel biomarkers for predicting the efficacy of immunotherapy combined with chemotherapy in GI cancer patients through 16S rRNA sequencing. Our findings demonstrated that lower baseline alpha diversity and specific microbial compositions, particularly lower levels of Lactobacillus , were significantly associated with longer progression‐free survival (PFS) in patients receiving immunotherapy combined with chemotherapy. Furthermore, we validated the reliability of Lactobacillus abundance as a predictor of PFS and treatment response in another independent patient cohort. Additionally, patients with increased or stable levels of Lactobacillus after immunotherapy combined with chemotherapy had superior PFS. Gavage of Lactobacillus rhamnosus (L. rhamnosus) el evated its blood level and enhanced the efficacy of immunotherapy in mouse models. Our results suggest that Lactobacillus may serve as a novel biomarker for predicting the efficacy of immunotherapy combined with chemotherapy and hold the potential as a PD‐1 antibody sensitizer.