Fecal microbiota transplantation for advanced non-small cell lung cancer with secondary PD-1 resistance efficacy prognostic factors and microbiome diversity analysis

Acquired resistance to programmed cell death protein 1 (PD-1) inhibitors represents a major therapeutic challenge in advanced non-small cell lung cancer (NSCLC). Increasing evidence suggests that gut microbiota dysbiosis contributes to immunotherapy resistance. Fecal microbiota transplantation (FMT) has emerged as a potential strategy to restore antitumor immunity, yet its role in PD-1–resistant NSCLC remains insufficiently explored. This prospective, single-arm phase II study enrolled patients with stage IIIB–IV NSCLC who developed secondary resistance after prior PD-1–based therapy. Patients received oral capsule-based FMT combined with PD-1 inhibitor rechallenge and chemotherapy. Treatment efficacy was assessed using objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Gut microbiota composition was analyzed by 16 S rRNA sequencing, and immune cell subsets were evaluated by flow cytometry. Cox regression analysis was performed to identify prognostic factors. A total of 27 patients were enrolled, of whom 8 achieved partial response, yielding an ORR of 29.6% and a disease control rate of 63.0%. Median PFS and OS were 6.8 months (95% CI: 2.1–11.6) and 11.1 months (95% CI: 6.4–15.9), respectively. Post-FMT, responders exhibited significantly increased gut microbial diversity and distinct microbial enrichment compared with non-responders. Enhanced infiltration of CD8⁺ T-cell subsets and reduced regulatory T-cell proportions were observed in responders. Multivariable analysis identified concomitant proton pump inhibitor use (HR: 12.67, P < 0.001) and corticosteroid exposure during FMT (HR: 4.98, P = 0.013) as independent predictors of shorter PFS. Treatment-related adverse events were common but mostly mild to moderate, with no FMT-related serious infections observed. FMT combined with PD-1 inhibitor rechallenge and chemotherapy demonstrated encouraging antitumor activity and acceptable safety in advanced NSCLC patients with secondary PD-1 resistance. Gut microbiota modulation may enhance immunotherapy responsiveness, while concomitant use of PPIs and corticosteroids may adversely affect outcomes. These findings support further investigation of microbiome-based strategies in overcoming immunotherapy resistance. National Health Security Information Platform and Medical Research Information System of China, MR3622010054.