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Background <p>Smoking status has been associated with differences in immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC), though the underlying mechanisms remain unclear. This prospective cohort study evaluated whether smoking-related changes in the gut microbiota are linked to ICI response.</p> Methods <p>Baseline fecal samples from 225 patients with NSCLC were analyzed using full-length 16S rRNA sequencing. Microbial composition, predicted functional features, and clinical variables were examined in relation to treatment response and progression-free survival (PFS). Associations with treatment response were assessed using multivariable ordinal logistic regression. PFS was evaluated using Kaplan–Meier analysis and the log-rank test.</p> Results <p>Smoking was associated with selected taxon-level microbial differences despite no significant differences in alpha or beta diversity. Compared with never-smokers, smokers exhibited reduced abundance of <i>Bifidobacterium longum</i> and enrichment of Gram-negative taxa. Functional prediction indicated increased potential for lipopolysaccharide, Kdo₂-lipid A, and lipid IVA biosynthesis in smokers. Predicted <i>lpxM</i> abundance, encoding a lipid A myristoyltransferase, was positively correlated with the Gram-negative bacterial fraction. Moreover, increased abundance of lpxM-linked Gammaproteobacteria was associated with improved ICI response in the NSCLC cohort. Conversely, lower <i>B. longum</i> abundance was associated with favorable ICI response and prolonged PFS.</p> Conclusions <p>These results indicate that smoking-related gut microbial alterations, particularly reduced <i>B. longum</i> abundance, are associated with enhanced ICI efficacy in NSCLC, supporting a role for the gut microbiota in smoking-associated differences in immunotherapy outcomes.</p>

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Smoking-associated modulation of gut microbiota shapes response to immune checkpoint inhibitors in non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月21日

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  • Po-Yu Chien,
  • Wen-Chien Cheng,
  • Chin-Chuan Hung,
  • Chih-Yen Tu,
  • Te-Chun Hsia,
  • Der-Yang Cho,
  • Po-Ren Hsueh,
  • Zi-Lun Lai,
  • Yi-Cheng Shen,
  • Yu-Chao Lin

摘要

Background

Smoking status has been associated with differences in immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC), though the underlying mechanisms remain unclear. This prospective cohort study evaluated whether smoking-related changes in the gut microbiota are linked to ICI response.

Methods

Baseline fecal samples from 225 patients with NSCLC were analyzed using full-length 16S rRNA sequencing. Microbial composition, predicted functional features, and clinical variables were examined in relation to treatment response and progression-free survival (PFS). Associations with treatment response were assessed using multivariable ordinal logistic regression. PFS was evaluated using Kaplan–Meier analysis and the log-rank test.

Results

Smoking was associated with selected taxon-level microbial differences despite no significant differences in alpha or beta diversity. Compared with never-smokers, smokers exhibited reduced abundance of Bifidobacterium longum and enrichment of Gram-negative taxa. Functional prediction indicated increased potential for lipopolysaccharide, Kdo₂-lipid A, and lipid IVA biosynthesis in smokers. Predicted lpxM abundance, encoding a lipid A myristoyltransferase, was positively correlated with the Gram-negative bacterial fraction. Moreover, increased abundance of lpxM-linked Gammaproteobacteria was associated with improved ICI response in the NSCLC cohort. Conversely, lower B. longum abundance was associated with favorable ICI response and prolonged PFS.

Conclusions

These results indicate that smoking-related gut microbial alterations, particularly reduced B. longum abundance, are associated with enhanced ICI efficacy in NSCLC, supporting a role for the gut microbiota in smoking-associated differences in immunotherapy outcomes.