Deciphering the gut-lung axis in non-small cell lung cancer: from immune microenvironment crosstalk to clinical translation
- 1School of Clinical Medicine, Shandong Second Medical University
- 2Department of Respiratory and Critical Care Medicine, Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences
Abstract
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.
Related
- Targeted protein degradation in cancer: strategies for undruggable targets and progress towards clinical translation.
- The Gut Microbiota-Immunity Axis in Colorectal Cancer: Implications for Immunotherapy and Clinical Translation.
- Magnetic Nanoparticles in Precision Cancer Therapy: From Synthesis and Biological Interactions to Clinical Translation
- Engineering extracellular vesicles for inflammatory bowel disease and colitis-associated colorectal cancer: from therapeutic innovation to clinical translation
- Label-free Raman spectroscopy for cancer therapy response: from methodological framework to clinical translation.
BibTeX
@article{sun2026deciphering,
title = {{Deciphering the gut-lung axis in non-small cell lung cancer: from immune microenvironment crosstalk to clinical translation}},
author = {Changrong Sun and Fei Han and Wenhao Xu and Xinliang Wang and Xin Wang},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1975256},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1975256/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Deciphering the gut-lung axis in non-small cell lung cancer: from immune microenvironment crosstalk to clinical translation
AU - Changrong Sun
AU - Fei Han
AU - Wenhao Xu
AU - Xinliang Wang
AU - Xin Wang
PY - 2026
DA - 2026/10/27
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1975256
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1975256/full
AB - 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.
SN - 2234-943X
ER -