SENP3 (SUMO specific peptidase 3) is a redox-sensitive desumoylase that specifically cleaves SUMO2 and SUMO3 conjugates from target proteins, with minimal activity against SUMO1 1. The enzyme functions as a critical regulator of cellular stress responses and immune functions through substrate-specific desumoylation. SENP3 enhances transcriptional activity by desumoylating proteins like MEF2D and EP300, and regulates ribosomal RNA processing through NPM1 desumoylation 1. In immune cells, SENP3 serves dual roles: it promotes antitumor immunity in dendritic cells by facilitating STING signaling through IFI204 desumoylation 2, while simultaneously regulating macrophage polarization and ferroptosis sensitivity through FSP1 desumoylation 3. Disease relevance includes significant upregulation in hepatocellular carcinoma, where SENP3 promotes oncogene translation via RACK1 desumoylation and facilitates immune evasion 4. The enzyme also contributes to abdominal aortic aneurysm development by destabilizing CTH through desumoylation, leading to enhanced ferroptosis 5. Clinically, elevated SENP3 expression correlates with poor prognosis in various cancers, making it an attractive therapeutic target for combination immunotherapies 41.