Gut microbiome and immunotherapy in advanced non–small cell lung cancer: a prospective cohort study

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The gut microbiome (GM) is increasingly recognized as a determinant of immune checkpoint inhibitor (ICI) efficacy in non–small cell lung cancer (NSCLC). However, most available evidence originates from Western, Bacteroides-dominant populations. Understanding GM characteristics in diverse ecological and dietary settings is crucial for global biomarker development. This is a prospective, observational study conducted at a tertiary cancer hospital. 50 adults with advanced NSCLC initiating PD-1/PD-L1 inhibitor–based therapy (with or without chemotherapy) between March 2024 and January 2025 were enrolled. Eligibility required ECOG performance status 0–2 and absence of concurrent antibiotics or probiotics. Paired stool samples were collected at baseline (T0) and first radiologic evaluation (T1, approximately 8–12 weeks). The aim was to characterize baseline and early-on-treatment gut microbiome composition and diversity in Indian patients with advanced NSCLC receiving ICI therapy and to explore associations with clinical outcomes between Responders (CR/PR/SD) vs. Non-Responders (PD). Among 50 enrolled patients (median age, 56 years; 52% male; 84% adenocarcinoma), 38 were responders and 12 nonresponders. The gut microbiome was Prevotella-dominant (P. copri ≈ 40% relative abundance). No significant differences in α-diversity (Shannon P = .47; Simpson P = .66) or β-diversity (PERMANOVA R²<0.03, P > .2) were observed. Nominal enrichment of Bacteroides sp. AM16 15, Holdemanella biformis, and Phocaeicola salanitronis was seen in responders, whereas Escherichia coli and other Proteobacteria were higher in some non-responders. Akkermansia muciniphila and Faecalibacterium prausnitzii showed no significant association with response. This first Indian NSCLC microbiome study establishes a Prevotella-rich regional baseline and underscores that microbiome–immunotherapy associations observed in Western cohorts may not be universal. Population-specific, functionally oriented, multi-omic studies are warranted to guide globally translatable microbiome-based interventions. The study was registered with Clinical Trial Registry of India (CTRI, 2024/03/081240) before starting enrolment in the study. Question:Does the gut microbiome composition of Indian patients with advanced NSCLC influence outcomes of immune checkpoint inhibitor therapy? Findings:In this prospective cohort of 50 patients, the gut microbiome was Prevotella-dominant, with no significant differences in α- or β-diversity between responders and nonresponders. Classical “Western” response-associated taxa such as Akkermansia muciniphila and Faecalibacterium prausnitzii were not predictive of response. Meaning:Population-specific microbiome baselines must inform biomarker development and future immunotherapy trials.

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