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<p>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. <i>Cordyceps sinensis</i> (<i>C. sinensis</i>), 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 <i>C. sinensis</i> 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, <i>C. sinensis</i>, 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 <i>C. sinensis</i> and anti-mouse PD-1 therapy in LLC mice were investigated using an integrated transcriptomics and metabolomics analysis. Treatment with anti-mouse PD-1, <i>C. sinensis</i>, or their combination significantly reduced tumor volume and weight, and attenuated the histopathological changes of LLC mice tumors. Among which, medium-dose <i>C. sinensis</i> combination exhibited significant improvements. Furthermore, the combination of <i>C. sinensis</i> and anti-mouse PD-1 significantly increased the proportion of CD8<sup>+</sup> T cells and decreased the abundance of Tregs and PMN-MDSCs. Integrated transcriptomics and metabolomics analysis revealed that the combination of <i>C. sinensis</i> 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 <i>C. sinensis</i> 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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月4日

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

摘要

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.