Unraveling gut microbiome interferences in cancer immunotherapy: a meta-analysis of diverse drug effects

Recent advancements in tumor therapy have centered on novel treatments, particularly immune checkpoint inhibitors (ICIs), which have transformed cancer treatment since their global approval in 2011. ICIs have demonstrated remarkable and substantial efficacy across a range of malignancies, including malignant melanoma, non-small cell lung cancer (NSCLC), head and neck cancers, renal carcinoma, and selected gastrointestinal cancers. Despite these promising outcomes, the challenges that during the clinical application, such as relatively low response rates and the occurrence of immune-related adverse events, can limit therapeutic benefits. Accumulating evidence highlights the gut microbiome as a critical modulator of cancer immunotherapy efficacy. Notably, alterations in gut microbiota composition observed in response to ICI therapy, and specific bacterial populations (such as an increased Clostridiales/ Baceroidales ratio, etc.) have been associated with improved responses in patients with NSCLC and renal cell carcinoma. However, the composition and function of the gut microbiome are influenced by a variety of factors, among which concomitant drug use plays a particularly prominent role. Medications commonly prescribed to cancer patients, such as antibiotics, proton pump inhibitors (PPIs), and probiotics, can significantly alter microbial communities, potentially impacting immunotherapy outcomes. Thus, there is a compelling need for rigorous research to elucidate how such drug-induced shifts in gut microbiota affect patient responses to ICIs. Thus, we conducted a meta-analysis which included 69 studies, 102 cohorts (22,568 patients were included) to systematically investigate the influence of drug interventions, including PPIs, antibiotics and probiotics on gut microbiome dynamics and ICI effectiveness. Progression-free survival (PFS), Overall survival (OS) and Objective response rate (ORR) were utilized as the main meta notions, while a subgroup analysis was determined based on: (1) tumor type; (2) exposure time window; (3) Treatment scheme as well. The total HR and 95% CI for PFS and OS are calculated separately for each intervention (probiotics, antibiotics, and PPIs) to compare their impact on ICI immunotherapy. Our research showed that the concurrent use of antibiotics or PPIs with ICIs was associated with significantly OS, PFS, and ORR. In contrast, probiotic supplementation demonstrated promising results with improved efficacy metrics. Besides, in subgroup analysis, patients using antibiotics within three months before or after the initiation of ICI therapy, OS, PFS, and ORR were significantly lower compared to those who did not receive antibiotics; the timing of antibiotic or PPI administration consistently resulted in poorer outcomes; a negative correlation between PPI use and OS, PFS, and ORR across treatment modalities was also exhibited. By elucidating the interplay between these factors, this study aims to provide robust evidence for optimizing ICI therapy, and to enlighten cancer treatment strategies more personalized, effective and safer, ultimately advancing patient care in oncology.