USP15 is a cysteine-type deubiquitinase that stabilizes substrate proteins through K48-linked and K63-linked deubiquitination 12. Its primary function involves regulating protein stability across multiple cellular contexts, including DNA damage responses, transcriptional regulation, metabolic pathways, and immune signaling 3. Mechanistically, USP15 interacts with and deubiquitinates key substrates to prevent proteasomal degradation. In DNA damage response, USP15 stabilizes ATM through K48-linked deubiquitination, promoting DNA repair 1. In developmental contexts, USP15 stabilizes the transcription factor TBX3 downstream of BRAF/MAPK signaling 4. USP15 also stabilizes PARP1 in triple-negative breast cancer, enhancing genomic stability and DNA repair 5. In metabolism, USP15 prevents ubiquitination-mediated degradation of the glycolytic regulator HKDC1 6. Clinically, USP15 overexpression associates with poor prognosis in multiple cancers. In colorectal cancer, USP15 promotes immune evasion by deubiquitinating SMYD3, increasing CCL2-mediated myeloid-derived suppressor cell recruitment and reducing CD8+ T-cell infiltration 7. Conversely, in pancreatic cancer, USP15 functions as a haploinsufficient tumor suppressor; loss of USP15 increases PARP inhibitor sensitivity 8. USP15 inhibitors represent promising therapeutic targets for enhancing immunotherapy and chemotherapy responses 76.