OTUD6B is a cysteine-type deubiquitinase with diverse cellular roles that vary significantly by cellular context and substrate. The protein functions as a positive regulator of innate immunity, where it stabilizes IRF3 by deubiquitinating K33-linked polyubiquitin chains at Lys315, enhancing type I interferon antiviral responses 1. OTUD6B promotes protein synthesis and cell proliferation through multiple mechanisms, including stabilization of RIPK1 in lung adenocarcinoma 2, deubiquitination of KIFC1 to support centrosome clustering in triple-negative breast cancer 3, and deubiquitination of β-TrCP to suppress SNAIL-mediated epithelial-mesenchymal transition in esophageal squamous cell carcinoma 4. Disease relevance is complex: OTUD6B overexpression predicts poor prognosis in lung adenocarcinoma and triple-negative breast cancer through tumor-promoting mechanisms 2 3. Conversely, low OTUD6B expression associates with poor prognosis in esophageal squamous cell carcinoma 4. In pulmonary arterial hypertension, increased OTUD6B promotes disease via the Calpain-1/HIF-1α pathway 5. The antisense RNA OTUD6B-AS1 functions as a tumor suppressor in thyroid carcinoma 6, while in colorectal cancer, OTUD6B stabilizes DDX5, recruiting CD8+ T cells and suppressing liver metastasis 7. These findings establish OTUD6B as a context-dependent regulator with potential therapeutic applications across multiple malignancies.