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Purpose <p>This study aimed to elucidate the biological mechanisms underlying the therapeutic effects of targeted alpha therapy (TAT) using a novel <sup>211</sup>At-labeled single-domain antibody drug ([<sup>211</sup>At]At-AuNP-sdAb). By integrating transcriptomic and metabolomic analyses, we sought to characterize the coordinated gene–metabolite responses induced by α-particle irradiation in melanoma models.</p> Methods <p>B16F10 melanoma cells and tumor-bearing mice were treated with [<sup>211</sup>At]At-AuNP-sdAb. RNA sequencing and untargeted LC–MS metabolomics were performed to identify differentially expressed genes and metabolites. Functional enrichment, OPLS-DA modeling, ROC curve analysis, and O2PLS-based multi-omics integration were used to explore the molecular networks and candidate indicators.</p> Results <p>[<sup>211</sup>At]At-AuNP-sdAb treatment significantly altered the transcription of 777 genes, revealing multi-dimensional cellular stress responses encompassing coordinated nuclear-cytoplasmic perturbations alongside downstream alterations in the mitochondrial respirasome and endoplasmic reticulum homeostasis. Untargeted metabolomic profiling revealed extensive metabolic reprogramming across amino acid, nucleotide, and lipid pathways, identifying key potential candidate indicators such as L-dihydroorotate, and Betaine. Furthermore, O2PLS integration successfully decoded robust multi-system covariance networks, wherein candidate distal metabolic nodes like glucosamine-6-phosphate demonstrated strong correlations with gene clusters regulating microenvironment remodeling.</p> Conclusion <p>[<sup>211</sup>At]At-AuNP-sdAb induces multi-dimensional cellular stress and extensive metabolic reprogramming characterized by concurrent genomic damage, subcellular organelle perturbations, and microenvironmental remodeling. The decoded multi-omics covariance networks and specific candidate indicators provide a comprehensive molecular landscape of α-particle-induced biological responses, offering valuable candidate frameworks for monitoring and evaluating TAT therapeutic outcomes.</p> Graphical Abstract <p></p>

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An integrative multi-omics landscape of multi-dimensional cellular stress and metabolic reprogramming in melanoma treated with targeted alpha therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Jiajia Zhang,
  • Zhiling Song,
  • Zhengguo Chen,
  • Xiaohui Luan,
  • Yuying Yu,
  • Xuhao Huang,
  • Jie Lye,
  • Jianguo Li,
  • Jie Gao,
  • Yuanyou Yang,
  • Kazuya Kabayama,
  • Koichi Fukase,
  • Ning Liu,
  • Feize Li,
  • Fei Yu

摘要

Purpose

This study aimed to elucidate the biological mechanisms underlying the therapeutic effects of targeted alpha therapy (TAT) using a novel 211At-labeled single-domain antibody drug ([211At]At-AuNP-sdAb). By integrating transcriptomic and metabolomic analyses, we sought to characterize the coordinated gene–metabolite responses induced by α-particle irradiation in melanoma models.

Methods

B16F10 melanoma cells and tumor-bearing mice were treated with [211At]At-AuNP-sdAb. RNA sequencing and untargeted LC–MS metabolomics were performed to identify differentially expressed genes and metabolites. Functional enrichment, OPLS-DA modeling, ROC curve analysis, and O2PLS-based multi-omics integration were used to explore the molecular networks and candidate indicators.

Results

[211At]At-AuNP-sdAb treatment significantly altered the transcription of 777 genes, revealing multi-dimensional cellular stress responses encompassing coordinated nuclear-cytoplasmic perturbations alongside downstream alterations in the mitochondrial respirasome and endoplasmic reticulum homeostasis. Untargeted metabolomic profiling revealed extensive metabolic reprogramming across amino acid, nucleotide, and lipid pathways, identifying key potential candidate indicators such as L-dihydroorotate, and Betaine. Furthermore, O2PLS integration successfully decoded robust multi-system covariance networks, wherein candidate distal metabolic nodes like glucosamine-6-phosphate demonstrated strong correlations with gene clusters regulating microenvironment remodeling.

Conclusion

[211At]At-AuNP-sdAb induces multi-dimensional cellular stress and extensive metabolic reprogramming characterized by concurrent genomic damage, subcellular organelle perturbations, and microenvironmental remodeling. The decoded multi-omics covariance networks and specific candidate indicators provide a comprehensive molecular landscape of α-particle-induced biological responses, offering valuable candidate frameworks for monitoring and evaluating TAT therapeutic outcomes.

Graphical Abstract