Deciphering the gut-lung axis in non-small cell lung cancer: from immune microenvironment crosstalk to clinical translation

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have established a new standard of care for non-small cell lung cancer (NSCLC); however, clinical efficacy is frequently limited by primary resistance, acquired (secondary) resistance, and immune-related adverse events. The heterogeneity of the tumor immune microenvironment (TIME) is a critical determinant of therapeutic response, a state effectively regulated by the gut microbiota via the gut-lung axis. This review systematically examines the mechanistic crosstalk between intestinal commensals and the pulmonary TIME. We first delineate how specific bacterial metabolites, such as short-chain fatty acids and indole-3-acetic acid, alongside bacterial-fungal trans-kingdom interactions, modulate innate and adaptive immune responses within the lung through epigenetic remodeling and metabolic signaling, and we map the discrete points at which these gut-derived signals converge on the intrinsic metabolic programmes of pulmonary tumor cells. Furthermore, we analyze the dual role of the microbiome as a predictive biomarker, discussing the evolution from simple taxonomic abundance profiling to complex ecological topology scores and the identification of therapeutic toxicity driven by molecular mimicry, and we examine whether pre-intervention alpha or beta diversity metrics are required for patient selection. Finally, we evaluate emerging therapeutic strategies, including next-generation probiotics, bacterial-derived extracellular vesicles, and combinational interventions that aim to overcome ICI resistance by restructuring the host-microbe ecosystem, with particular attention to acquired resistance to PD-1 blockade. We also critically appraise the barriers that currently impede clinical translation, including the inter-cohort non-reproducibility of taxonomic biomarkers, methodological heterogeneity between 16S amplicon and shotgun metagenomic profiling, and the safety and regulatory constraints on fecal microbiota transplantation in immunocompromised patients. This synthesis underscores the necessity of integrating microbiome profiling into standard oncological practice to facilitate precision immunotherapy.