Immunomodulatory mechanisms of gut microbiota-derived metabolites in non-small cell lung cancer: a gut–lung axis perspective

Immunotherapy has emerged as a crucial component in the treatment of non-small cell lung cancer (NSCLC). Nevertheless, interindividual variability in efficacy, along with both primary and acquired resistance, as well as immune-related adverse events, continue to limit the benefits for patients. The gut microbiota and its associated metabolites are believed to play a significant role in pulmonary immune regulation via the gut–lung axis, with alterations in this system being associated with NSCLC development and progression, as well as the outcomes of immunotherapy. This review summarizes the key features of gut microbial and metabolic profiles in patients with NSCLC, focusing particularly on the mechanisms by which short-chain fatty acids, bile acids, gut microbiota-associated Trp metabolites, and other microbial metabolites may influence the tumor immune microenvironment and responses to immunotherapy. Furthermore, we consider their potential value in supporting NSCLC diagnosis, prognostic assessment, and treatment-response prediction. Therapies aimed at targeting metabolic pathways, fecal microbiota transplantation, dietary interventions, and microbiome-based preparations present additional avenues for enhancing the efficacy of NSCLC immunotherapy and managing treatment-related toxicity. However, current evidence primarily stems from small clinical studies and animal models, while methodological discrepancies and limited causal evidence impede clinical translation. Future research that integrates longitudinal multi-omics analyses, metabolic tracing, and controlled clinical trials is essential to elucidate the clinical significance of the gut microbiota-metabolite axis in NSCLC immunotherapy and precision medicine.