UBE2T (ubiquitin-conjugating enzyme E2 T) is an E2 ubiquitin-conjugating enzyme that catalyzes monoubiquitination and polyubiquitination of target proteins across multiple cellular pathways 1. Its canonical function involves catalyzing FANCD2 monoubiquitination as part of the Fanconi anemia DNA repair complex, a critical step in mitomycin-C-induced DNA damage responses 2. Beyond DNA repair, UBE2T mediates ubiquitination of diverse substrates including p53, Akt, H2AX, RACK1, and CDC42, affecting cellular metabolism, survival, and immune function 2345. UBE2T is significantly upregulated across multiple malignancies including pancreatic, hepatocellular, gastric, and triple-negative breast cancers, where elevated expression correlates with poor prognosis and therapy resistance 1. Mechanistically, UBE2T drives tumorigenesis by: (1) facilitating p53 degradation to promote pyrimidine biosynthesis and gemcitabine resistance in pancreatic cancer 2; (2) mediating H2AX monoubiquitination to activate CHK1-dependent DNA damage checkpoints, promoting radioresistance in hepatocellular carcinoma 3; and (3) regulating CDC42-mediated CD276 stability to suppress CD8+ T cell function and promote immune escape in brain metastasis 6. UBE2T inhibition potentiates chemotherapy and immunotherapy efficacy, establishing UBE2T as a promising therapeutic target 26.