Lung microbiota, gut microbiota, and the lung-gut axis in lung cancer immunotherapy: a tripartite regulatory perspective

The gut microbiota is well established as a key modulator of systemic immunity, with growing evidence supporting its impact on lung cancer immunotherapy outcomes. However, the contributions of the lung microbiota and the recently recognized intratumoral microbiota remain less defined. This review synthesizes current evidence on the gut-lung axis, consolidating the tripartite regulatory network of gut, lung, and intratumoral microbiota in shaping the lung cancer immune microenvironment and immunotherapy response. We discuss how gut-derived metabolites such as indole-3-propionic acid may remotely modulate CD8+ T cell stemness, how lung microbiota locally influence alveolar macrophage polarization through pattern recognition receptor signaling, and how intratumoral microbiota have been implicated in STING pathway activation, Treg/M2 polarization, and PD-L1 expression. Although these microbial communities are conceptually linked through the lung-gut axis, the empirical evidence supporting their integrated network remains preliminary, and the clinical relevance of these interactions requires further investigation. Future research should focus on establishing causal relationships between specific microbial taxa and immunotherapy outcomes, elucidating spatial heterogeneity through multi-omics approaches, and validating microbiota-targeted interventions in well-designed prospective studies. This review offers a framework for critically evaluating the current evidence and identifying key knowledge gaps in this evolving field.