Gut microbiome-driven modulation of the tumor immune microenvironment optimizes dual checkpoint blockade in advanced non-small-cell lung cancer

BACKGROUND: Dual checkpoint blockade with ipilimumab plus nivolumab (I-N), with or without chemotherapy, has shown clinical efficacy for treating advanced non-small-cell lung cancer (NSCLC); however, its benefits are limited to a subset of patients. The gut microbiome influences immune responses and may impact the efficacy of immune checkpoint inhibitors, thus warranting further investigation. MATERIALS AND METHODS: This prospective study enrolled 50 patients with NSCLC who were treated with I-N, with and without chemotherapy. Gut microbiota diversity and composition were assessed from fecal samples collected before treatment initiation, and tumor-infiltrating lymphocytes (TILs) were evaluated using multiplex immunofluorescence staining. Progression-free survival (PFS), overall survival (OS), and objective response rate were analyzed alongside gut microbiota characteristics and treatment regimens. RESULTS: High gut microbiota diversity was associated with improved outcomes in patients receiving I-N alone and with greater CD8+ TIL infiltration, particularly PD-1+CD8+ TILs. Responders receiving I-N alone showed enrichment of short-chain fatty acid (SCFA)-producing bacteria, which were linked to favorable metabolic pathways associated with antitumor immune responses. In contrast, the association between gut microbiota diversity and treatment efficacy was not observed in patients treated with I-N plus chemotherapy. Antibiotic use before treatment was independently associated with shorter PFS and OS across all treatment regimens. CONCLUSIONS: Gut microbiota diversity and SCFA-producing bacteria are associated with improved efficacy of I-N. Baseline gut microbiota diversity may help identify patients who are more likely to have improved outcomes with I-N plus chemotherapy than with I-N alone. These findings highlight the potential of gut microbiota as a novel biomarker for dual checkpoint blockade in NSCLC may contribute to advancing personalized medicine.