Shuyu Wan Potentiates PD-1 Inhibitor Efficacy in Non-Small Cell Lung Cancer: Integrated Bioinformatics and Experimental Evidence for Gut Microbiota-Tumor Immune Crosstalk.

Authors

Tianqing Sang, Yajing Li, Qihan He, Wei Wu, Qijun Fang, Yinglu Liu, Lijun Yue, Lijing Shi, Lifang Mei, Chubo Huang, Huang Huang, Huajun Zhang, Qian Wan, Yigang Wan

Published in

Drug design, development and therapy. Volume 20. Pages 617793. Epub Jul 08, 2026.

Abstract

Therapeutic heterogeneity limits the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Shuyu Wan (SYW), a classic TCM formula, has shown potential in modulating gut microbiota (GM) and enhancing immunotherapy, yet its synergistic mechanism with PD-1 inhibitors remains unclear.
SYW components were identified by UPLC-MS. NSCLC-related targets were integrated with SYW targets for pathway enrichment, and molecular docking validated component-target binding. NSCLC syngeneic mice were treated with SYW and/or PD-1 inhibitor (RMP1-14). Tumor growth, histopathology, serum cytokines, tumor-infiltrating CD8⁺T cell subsets (flow cytometry), PD-1/PD-L1 expression and co-localization (immunofluorescence), GM composition (16S rRNA), and metabolomics were assessed. FMT verified the role of GM-TME crosstalk.
SYW monotherapy showed no significant tumor inhibition, whereas SYW combined with PD-1 inhibitor dose-dependently suppressed NSCLC growth. The combination reduced PD-1 expression and PD-1/PD-L1 co-localization, elevated serum IL-12, IFN-γ, and TNF-α, increased total tumor-infiltrating CD8⁺ T cells, decreased PD-1⁺ and TIM-3⁺ exhausted subsets, and expanded IFN-γ⁺ and Granzyme B⁺ effector subsets. Concurrently, it reshaped GM (increased Bacillota, decreased Patescibacteria) and altered metabolites (L-glycine, L-proline). These effects were abolished in antibiotic treated mice and restored by FMT, suggesting GM-TME crosstalk as essential.
SYW acts as a microbiota-dependent immune sensitizer that potentiates PD-1 inhibitor efficacy in NSCLC by remodeling GM and enhancing effector CD8⁺ T cell infiltration while reducing exhaustion. GM-TME crosstalk is the potential mechanism, supporting SYW as an adjunct to PD-1 blockade in NSCLC therapy.

PMID:
42438795
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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