Transcriptomic Profiling Reveals Ferroptosis-Associated Redox Disruption and Immune Activation Induced by 177Lu-SiMS@FMT
To elucidate the molecular mechanisms underlying the potent antitumor activity of 177Lu-SiMS@FMT, we performed transcriptomic RNA-sequencing on tumor tissues from control and treated groups. Principal component analysis (PCA) demonstrated robust separation between the two groups, confirming a distinct transcriptional landscape induced by treatment. Differential expression analysis identified 3,212 upregulated and 1,581 downregulated genes, revealing extensive transcriptional reprogramming. Notably, genes involved in antioxidant defense, including Gpx4, Slc7a11, and Gss, were significantly downregulated, whereas key components of the cGAS-STING innate immune pathway, including Sting1, Tbk1, and Irf3, were markedly upregulated. Gene Ontology (GO) enrichment analysis indicated that differentially expressed genes were enriched in cell death, oxidoreductase activity, glutathione metabolism, lipid oxidation, and immune system processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further revealed significant enrichment of glutathione metabolism and NOD-like receptor signaling pathways. Gene Set Enrichment Analysis (GSEA) confirmed negative enrichment of glutathione metabolism and positive enrichment of immune-associated Rap1 signaling. Collectively, these transcriptomic data demonstrate that 177Lu-SiMS@FMT simultaneously disrupts cellular antioxidant capacity and activates innate immune signaling within the tumor microenvironment, providing a mechanistic basis for its dual ferroptosis-immunotherapeutic efficacy.