Microbiome and EGFR-mutant non-small cell lung cancer: a complex interplay

Introduction: Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) exhibits unique biological and therapeutic characteristics. Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) offer substantial clinical benefits, resistance development and treatment-related toxicities remain major challenges. Emerging evidence indicates that the host microbiome may significantly influence the efficacy and tolerability of EGFR-targeted therapies. Areas covered: This review summarizes the main microbiome characteristics of EGFR-mutant NSCLC and discusses the interplay between gut, respiratory and intratumoral microbiome and EGFR-TKI therapy in NSCLC, highlighting differential microbiome shifts associated with different TKIs and comparing the role of microbiome in modulating responses to EGFR-TKIs. The review also explores preclinical and early clinical strategies aimed at enhancing TKI efficacy and at, potentially, improving sensitivity of EGFR-mutant NSCLC to immunotherapy. Expert opinion: Despite its emerging role, microbiome research in EGFR-mutant NSCLC holds substantial potential to refine therapeutic outcomes. Microbiota-targeted interventions may improve TKIs efficacy, mitigate toxicity, and potentially expand immunotherapeutic options in this molecularly and immunologically 'cold' subgroup. Future integrative studies combining microbiome, metabolome and immune profiling are essential to translate these insights into personalized clinical strategies.