The microbiome and brain metastasis in non‐small cell lung cancer: A graded appraisal and a framework for prevention‐oriented research

Background Brain metastasis remains a major cause of mortality and treatment failure in non‐small cell lung cancer (NSCLC). However, current models of cerebral dissemination rarely integrate microbiome‐dependent systemic and intratumoral biology.This Review examines the potential microbiome‐brain metastasis axis linking gut, lung, and intratumoral microbial communities to intracranial dissemination and therapeutic response. Methods A reproducible literature search was conducted to evaluate proposed mechanisms underlying microbiome‐associated brain metastasis. Evidence for each mechanistic claim was graded using a four‐level evidence scheme (E1‐E4), while microbial detection confidence was assessed using a four‐tier hierarchy (D1‐D4). Results No component of the proposed axis reached E1 evidence, and all published microbial observations in NSCLC brain metastasis rests on nucleic‐acid detection alone. Five mechanisms are examined: circulating microbial metabolites acting on endothelial permeability and glial reactivity; microbiome‐imprinted immune‐cell trafficking;intracellular bacteria within primary lung tumours; cross‐kingdom MR1/MAIT and Dectin‐CARD9 signalling; and candidate host genetic determinants. The available human data are small, single‐centre and cross‐sectional, reporting association with brain‐metastasis status rather than prediction or causation; that bacteria accompany disseminating tumour cells into the brain remains a hypothesis awaiting paired sampling, spatial localization and experimental perturbation.We therefore reserve the term prevention for proposed trials, integrate microbial features with established molecular risk models, and specify the genetic‐perturbation program and research‐only decision pathway that would convert these claims into E1 evidence. Conclusions The microbiome–brain metastasis axis provides a hypothesis‐generating framework for investigating microbial contributions to cerebral dissemination. Multi‐centre validation, paired primary‐brain metastasis profiling and gnotobiotic models are required before microbiome‐directed strategies can be said to improve intracranial outcomes;until then this framework is hypothesis‐generating, not practice‐changing. Key points The proposed microbiome–brain metastasis axis links gut, lung and intratumoral microbial communities to intracranial dissemination in NSCLC. Current evidence remains insufficient to establish causality, with no proposed mechanism reaching the highest evidence level (E1). Five candidate mechanisms involve microbial metabolites, immune‐cell trafficking, intratumoral bacteria, MR1/MAIT and Dectin‐CARD9 signalling, and host genetic determinants. Multicentre validation, paired primary and brain metastasis profiling, spatial microbial localisation and experimental perturbation are needed to establish causality and assess clinical relevance. Microbiome‐directed prevention and therapeutic strategies remain investigational and should not yet inform routine clinical practice.