Protein Ubiquitination in Tumor Initiation, Malignant Progression, and Targeted Therapy

Protein ubiquitination is a reversible post-translational modification that controls protein stability, subcellular localization, signaling complex assembly, and proteasome-dependent degradation. In cancer, altered ubiquitin signaling reshapes core oncogenic programs by regulating tumor suppressors, cell-cycle proteins, transcription factors, DNA damage response components, immune checkpoints, inflammatory mediators, and angiogenic regulators. Recent advances have clarified how ubiquitin chain topology, degron recognition, E3 ubiquitin ligase specificity, and deubiquitinase activity determine substrate fate rather than simply marking proteins for destruction. Dysregulated ubiquitination supports sustained proliferation, epithelial-mesenchymal plasticity, metastatic colonization, immune escape, therapy resistance, and tumor microenvironment remodeling. These mechanisms have also generated therapeutic opportunities. Proteasome inhibitors remain clinically relevant in selected hematologic malignancies, while E3 ligase modulators, deubiquitinase inhibitors, molecular glues, and proteolysis-targeting chimeras have expanded the druggable space to transcription factors, scaffolding proteins, mutant oncoproteins, and lineage-specific dependencies. This review summarizes recent progress in ubiquitination biology in cancer, with emphasis on enzymatic regulation, tumor-cell intrinsic malignant phenotypes, inflammatory and immune control, angiogenesis, and therapeutic strategies based on the ubiquitin-proteasome system and targeted protein degradation.