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Cordyceps sinensis enhances the efficacy of anti-PD-1 immunotherapy in Lewis lung adenocarcinoma
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  • Published: 04 February 2026

Cordyceps sinensis enhances the efficacy of anti-PD-1 immunotherapy in Lewis lung adenocarcinoma

  • Yingying Liu1,2,3,
  • Yaqi Gao1,2,3,
  • Suonanlamao4,
  • Yuanan Ma1,2,3,
  • Yuancan Xiao1,2,
  • Lixin Wei1,2 &
  • …
  • Wenbin Zhou1,2 

Scientific Reports , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer
  • Drug discovery
  • Immunology
  • Oncology

Abstract

Lung cancer, primarily non-small cell lung cancer (NSCLC), causes the highest cancer-related mortality. Although PD-1/PD-L1 inhibitors have improved survival in advanced NSCLC, they can cause immune-related adverse events. Cordyceps sinensis (C. sinensis), a traditional Chinese medicine used for tonifying the lung and kidney and enhancing immune function, has shown therapeutic promise in combination with anti-PD-1 therapy for NSCLC. This study aimed to explore the anti-tumor effect of wild C. sinensis combined with anti-mouse PD-1 in the treatment of Lewis lung adenocarcinoma (LLC) and to elucidate the underlying pharmacodynamic mechanism. LLC mouse model was established via inoculation with LLC cells, followed by treatment with anti-mouse PD-1, C. sinensis, or their combination. The tumor volume, weight, and histological changes of LLC mice were evaluated. The proportions of tumor-infiltrating immune cells in blood and tumors were evaluated by flow cytometry, immunohistochemistry, and immunofluorescence. The underlying mechanisms of the combination of C. sinensis and anti-mouse PD-1 therapy in LLC mice were investigated using an integrated transcriptomics and metabolomics analysis. Treatment with anti-mouse PD-1, C. sinensis, or their combination significantly reduced tumor volume and weight, and attenuated the histopathological changes of LLC mice tumors. Among which, medium-dose C. sinensis combination exhibited significant improvements. Furthermore, the combination of C. sinensis and anti-mouse PD-1 significantly increased the proportion of CD8+ T cells and decreased the abundance of Tregs and PMN-MDSCs. Integrated transcriptomics and metabolomics analysis revealed that the combination of C. sinensis and anti-mouse PD-1 can enhance anti-tumor immunity in LLC mice by acting on key immune-related genes, including DGKA, PLA2G7, AMPD1, ATP8B4, and BST1, thereby modulating glycerophospholipid metabolism, the TCA cycle, purine metabolism, and nicotinate-nicotinamide metabolism. Wild C. sinensis combined with anti-mouse PD-1 therapy exerts therapeutic effects against LLC by targeting immune-related genes, modulating associated pathways, increasing the proportion of CD8+ T cells, and reducing the infiltration of Tregs and PMN-MDSCs, thereby suppressing tumor growth and inhibiting LLC progression. Further research and clinical studies are needed to validate and expand upon these promising findings.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

NSCLC:

Non-small cell lung cancer

ICIs:

Immune checkpoint inhibitors

PD-1:

Programmed cell death-1

PD-L1:

Programmed cell death ligand 1

C. sinensis :

Cordyceps sinensis

DAB:

Diaminobenzidine

DEGs:

Differentially expressed genes

FC:

Flow cytometry

LLC:

Lewis lung adenocarcinoma

LC:

Lung cancer

TCMs:

Traditional Chinese medicines

TGI:

Tumor growth inhibition rate

H&E:

Hematoxylin-eosin

ES:

Enrichment scores

QC:

Quality control

OPLS-DA:

Orthogonal partial least squares discriminant analysis

PCA:

Principal component analysis

PLS-DA:

Partial least squares discriminant analysis

VIP:

Variable importance in projection

IHC:

Immunohistochemistry

IF:

Immunofluorescence

TME:

Tumor microenvironment

PMN-MDSCs:

Polymorphonuclear myeloid-derived suppressor cells

Tregs:

Regulatory T cells

RNA-Seq:

RNA sequencing

NLRs:

NOD-like receptors

NK:

Natural killer

FMN:

Flavin mononucleotide

FAD:

Flavin adenine dinucleotide

SD:

Standard deviation

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Acknowledgements

This work has been supported by Major Science and Technology Project of Qinghai Province (NO. 2021-SF-A4), Chinese Academy of Sciences - People’s Government of Qinghai Province on Sanjiangyuan National Park (NO. LHZX-2022-01), and Qinghai Association for Science and Technology Youth and Middle-aged Talent Support Program (NO. 2022QHSKXRCTJ35). We also acknowledge our colleagues for their work on this paper.

Funding

This work has been supported by Major Science and Technology Project of Qinghai Province (NO. 2021-SF-A4), Chinese Academy of Sciences - People’s Government of Qinghai Province on Sanjiangyuan National Park (NO. LHZX-2022-01), and Qinghai Association for Science and Technology Youth and Middle-aged Talent Support Program (NO. 2022QHSKXRCTJ35).

Author information

Authors and Affiliations

  1. Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Science, Xining, 810008, Qinghai, China

    Yingying Liu, Yaqi Gao, Yuanan Ma, Yuancan Xiao, Lixin Wei & Wenbin Zhou

  2. CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008, China

    Yingying Liu, Yaqi Gao, Yuanan Ma, Yuancan Xiao, Lixin Wei & Wenbin Zhou

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yingying Liu, Yaqi Gao & Yuanan Ma

  4. College of Tibetan Medicine, Qinghai University, Xining, 810016, China

    Suonanlamao

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Contributions

Conceptualization: W.Z. Data curation: Y.L. Formal analysis: Y.L., Y.G., S.L., Y.M., and W.Z. Funding acquisition: L.W., and W.Z. Investigation: Y.L., Y.G., S.L., Y.M., Y.X., and W.Z. Methodology: Y.L. Resources: L.W. Supervision: L.W. Writing – original draft: Y.L., and W.Z. Writing – review & editing: L.W., and W.Z.

Corresponding authors

Correspondence to Lixin Wei or Wenbin Zhou.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent for publication

This study was approved by the Animal Experimentation Committee of Northwest Plateau Biology Institute, Chinese Academy of Sciences (allowance number NWIPB2023–19).

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Liu, Y., Gao, Y., Suonanlamao et al. Cordyceps sinensis enhances the efficacy of anti-PD-1 immunotherapy in Lewis lung adenocarcinoma. Sci Rep (2026). https://doi.org/10.1038/s41598-026-37878-0

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  • Received: 05 October 2025

  • Accepted: 27 January 2026

  • Published: 04 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-37878-0

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Keywords

  • Cordyceps sinensis
  • Anti-mouse PD-1
  • Lewis lung adenocarcinoma
  • Transcriptomics
  • Metabolomics
  • Anti-tumor effect
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