Abstract
Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death globally. Although the gut microbiota's role in the antitumor efficacy of many cancers has been revealed, its involvement in the response to gefitinib therapy for LUAD remains unclear. To fill this gap, we conducted a longitudinal study that profiled gut microbiota changes in PC-9 tumor-bearing mice under different treatments, including gefitinib monotherapy and combination therapies with probiotics, antibiotics, or Traditional Chinese Medicine (TCM). Our findings demonstrated that combining probiotics or TCM with gefitinib therapy outperformed gefitinib monotherapy, as evidenced by tumor volume, body weight, and tumor marker tests. By contrast, antibiotic intervention suppressed the antitumor efficacy of gefitinib. Notably, the temporal changes in gut microbiota were strongly correlated with the different treatments, prompting us to investigate whether there is a causal relationship between gut microbiota and the antitumor efficacy of gefitinib using Mediation Analysis (MA). Finally, our research revealed that thirteen mediators (Amplicon Sequence Variants, ASVs) regulate the antitumor effect of gefitinib, regardless of treatment. Our study provides robust evidence supporting the gut microbiota's significant and potentially causal role in mediating gefitinib treatment efficacy in mice. Our findings shed light on a novel strategy for antitumor drug development by targeting the gut microbiota.