Drug-regulated protein post-translational modifications (PTMs) enable the identification of modulated pathways and the revealing of phenotypic responses for the disease. However, the integrated regulatory mechanisms of radiopharmaceuticals across proteomic and PTMs landscapes remain poorly characterized. To address this gap, this study presents a quantitative multi-level proteomic analysis to assess regulated PTMs and pathway engagement. Quantitative glycoproteomics, phosphoproteomics, and global proteomics were performed using tumor tissues from radiopharmaceutical-treated mouse models. By analyzing the subcellular signaling pathways with site-specific PTMs, differentially expressed molecular signatures were identified with radiopharmaceutical action. Our study provides comprehensive landscape of the global proteome and PTMs-proteome for radiopharmaceuticals regulation. These findings uncover multi-level cellular molecular mechanisms involving DNA repair, extracellular matrix organization, and metabolic regulation. These findings elucidate the molecular mechanism of radiopharmaceuticals at the proteomic and PTMs-proteomic levels, offering valuable insights for radiopharmaceutical development.