Abstract
BACKGROUND: Lung cancer is the leading cause of cancer-related mortality globally, with lung adenocarcinoma (LUAD) as the most common subtype. Dysbiotic intratumoral mycobiomes drive LUAD pathogenesis, and Aspergillus sydowii (A. sydowii) acts as a key oncogenic fungal species. Ginseng polysaccharides (GPs), bioactive phytochemicals with immunomodulatory and oncostatic properties, counteract fungal infections and restore immunosurveillance in LUAD. METHODS: Subcutaneous and orthotopic LUAD murine models were established by implanting Lewis lung carcinoma (LLC) cells. Subcutaneous tumors were infected intratumorally and orthotopic models via nasal inoculation. GPs (200 mg/kg/day) were orally administered to evaluate tumor growth. Metagenomic and targeted bile acid metabolomic profiling of fecal and tumor tissues was performed, with Spearman correlations analyzed using R packages. RESULTS: GPs significantly inhibited A. sydowii-induced tumor growth in both models. In subcutaneous tumors; GPs reduced volume (p < 0.05) and weight vs. infected controls. In orthotopic models, GPs decreased pathological nodules and lung weight, with micro-CT/H&E confirming attenuated hyperplasia. Metagenomics showed GPs restored gut homeostasis by enriching Lactobacillus/Muribaculum intestinale and suppressing pro-inflammatory Alistipes. Targeted metabolomics revealed reduced β-Hyodeoxycholic Acid (3β-HDCA), Chenodeoxycholic acid 24-acyl-b-D-glucuronide (CDCA-24G) and 3β-hydroxychol-5-en-24-oic acid (5-isoLCA) after GP treatment. Network analysis confirmed significant microbe-bile acid interactions. CONCLUSIONS: GPs exert antitumor effects against A. sydowii-induced LUAD by modulating gut microbiota and bile acid metabolism. This identifies GPs as a promising therapy for mycobiome-influenced cancers, with dual targeting of fungal infection and metabolic reprogramming.