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

This study aimed to elucidate the biological mechanisms underlying the therapeutic effects of targeted alpha therapy (TAT) using a novel 211 At-labeled single-domain antibody drug ([ 211 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. B16F10 melanoma cells and tumor-bearing mice were treated with [ 211 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. [ 211 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. [ 211 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.