Gut-Lung Microbiota Axis Shapes the Immune Microenvironment and Immunotherapeutic Response in Lung Cancer

TL;DR

The gut and lung microbiota influence lung cancer progression and immunotherapy response by shaping the immune environment and affecting immune cell activity.

Contribution

This review highlights the role of gut-lung microbiota in immunotherapy response and tumor immunity in lung cancer.

Findings

Lung cancer patients show altered microbial signatures with specific taxa like Streptococcus and Bacteroidetes.

Beneficial microbes like Akkermansia muciniphila enhance immunotherapy response by boosting CD8⁺ T cells.

Microbial metabolites and pathways like cGAS-STING modulate immune responses and tumor progression.

Abstract

The gut-lung axis microbiota plays a pivotal role in shaping the tumor immune microenvironment (TIME) and regulating immunotherapeutic responses in lung cancer. This review highlights that pulmonary and gut microbial dysbiosis drives lung cancer development through inducing chronic inflammation, remodeling the immune microenvironment, and reprogramming metabolism. Lung cancer patients exhibit distinct microbial signatures characterized by altered microbiotal diversity and enrichment of specific taxa like Streptococcus, Veillonella, and Bacteroidetes in the airways, along with gut microbial shifts involving decreased Firmicutes/Bacteroidetes ratio. These microbial alterations promote tumor progression via activation of pro-inflammatory pathways (e.g., interleukin-17 (IL-17)/interleukin-23 (IL-23) axis) and suppression of antitumor immunity.Notably, the gut-lung microbiome exerts a profound impact on immunotherapeutic efficacy: responders are enriched with beneficial microbes like Akkermansia muciniphila and Bifidobacterium that enhance CD8⁺ T cell responses, while non-responders show elevated levels of Gammaproteobacteria and Fusobacterium associated with immunosuppression. Regulatory mechanisms include systemic immune modulation by microbial metabolites such as short-chain fatty acids, as well as activation of key signaling pathways including cGAS-STING and CD40L-CD40/NF-κB. Emerging translational applications encompass lung cancer diagnosis and immunotherapeutic response prediction via microbial biomarkers, as well as therapeutic interventions including fecal microbiota transplantation (FMT) and probiotic supplementation. Future studies should clarify microbe-host interaction mechanisms and develop personalized microbiota-based strategies to overcome immunotherapy resistance, offering the potential to revolutionize precision oncology through integrating microbiota modulation with conventional therapies.

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