Harnessing Gut Microbiota to Enhance Immunotherapy in NSCLC: From Mechanisms to Translational Applications

The gut microbiome has emerged as a pivotal regulator of immunotherapy efficacy in non-small cell lung cancer (NSCLC), with mounting evidence demonstrating that microbial-immune crosstalk significantly influences therapeutic responses. Current research reveals that commensal bacteria modulate host immunity through complex metabolic and immunological pathways, yet the precise mechanisms underlying these interactions remain incompletely characterized. Meanwhile, the substantial heterogeneity of microbial ecosystems across individuals and the lack of standardized protocols for microbiota-based therapeutic interventions pose significant barriers to clinical translation. Furthermore, unresolved questions persist regarding the safety profiles and reproducibility of clinical outcomes associated with microbial modulation. Addressing these knowledge gaps could provide transformative insights into immunotherapy resistance while enabling the development of precision medicine approaches. This narrative review synthesizes current knowledge on the clinical impact of gut microbiota on the immunotherapy response in NSCLC, mechanistic insights into the interactions between gut microbiota and the lung cancer immune microenvironment, and the challenges in clinical translation. By integrating these perspectives, we develop a practical framework for implementing microbiota-based strategies to enhance immunotherapy efficacy, with the hope of addressing current limitations in biomarker development, intervention protocols, and personalized treatment approaches to bridge the gap between research and clinical practice in precision oncology.