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Microbial metabolites and the gut-lung axis in non-small cell lung cancer immunotherapy: evidence boundaries and
Fangxiong Zheng1,2, Yuchen Zhang2, Zhongxin Lu1,2
1Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Immune checkpoint inhibitors (ICIs) have changed the treatment of non-small cell lung cancer (NSCLC), but response, acquired resistance and immune-related adverse events (irAEs) remain variable. Gut microbiome features and microbial metabolites may contribute to this variation through systemic immunity, gut-lung communication and the tumor immune microenvironment. This structured narrative review synthesizes direct and near-direct NSCLC or lung-cancer immunotherapy evidence, including cohorts ranging from 37 to 556 patients, a phase III chemoimmunotherapy ancillary cohort with 270 baseline fecal samples and recent TOPOSCORE-based community-ecology studies. Clinical evidence reports recurrent but inconsistent associations among microbial diversity, Akkermansia-related states, community topology, functional microbial features, survival, treatment-duration questions and toxicity, with substantial variation by region, treatment setting and endpoint. Mechanistic studies support plausible pathways involving short-chain fatty acids (SCFAs), bile acids, tryptophan-related metabolites, inosine and exploratory bacterial extracellular vesicle-associated signals. Few studies, however, connect microbiome, metabolite, immune and clinical outcome data within the same patients. We use an evidence-boundary framework to state what each evidence layer can support. In the current evidence base, microbiome signals are better suited to prospective validation, trial design and communication of uncertainty than to routine microbiome testing or intervention outside regulated studies.
Insights
The gut microbiome influences non-small cell lung cancer (NSCLC) immunotherapy response and side effects, but findings are inconsistent. More research is needed to connect microbiome data with clinical outcomes for better patient treatment.
Area of Science:
- Oncology
- Immunology
- Microbiome Research
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized non-small cell lung cancer (NSCLC) treatment.
- Variability in patient response, resistance, and immune-related adverse events (irAEs) to ICIs persists.
- The gut microbiome and its metabolites are implicated in modulating systemic immunity and the tumor microenvironment.
Purpose of the Study:
- To synthesize current evidence on the role of the gut microbiome in NSCLC immunotherapy.
- To evaluate associations between microbial features, metabolites, and clinical outcomes in NSCLC patients receiving immunotherapy.
- To delineate the strengths and limitations of existing evidence for clinical application.
Main Methods:
- Structured narrative review of direct and near-direct evidence in NSCLC or lung cancer immunotherapy.
- Inclusion of clinical cohorts (N=37-556), a phase III chemoimmunotherapy ancillary study (N=270 fecal samples), and community-ecology studies.
- Analysis of evidence linking microbiome composition, metabolites, immune responses, and clinical endpoints.
Main Results:
- Recurrent but inconsistent associations were found between microbial diversity, specific bacteria (e.g., Akkermansia), community topology, functional features, survival, and toxicity.
- Mechanistic pathways involving short-chain fatty acids (SCFAs), bile acids, tryptophan metabolites, and inosine are supported.
- A significant gap exists in studies integrating microbiome, metabolite, immune, and clinical data within the same patient cohorts.
Conclusions:
- Current evidence suggests microbiome signals are more suitable for prospective validation and trial design than routine clinical testing.
- Substantial variation in findings necessitates careful consideration of region, treatment setting, and endpoint.
- Further research is required to establish robust connections between the gut microbiome and NSCLC immunotherapy outcomes.