SETD2 is a histone H3K36 trimethyltransferase that catalyzes H3K36me3, a critical mark of active transcription 1. As a component of the RNA polymerase II elongation machinery, SETD2 is recruited to transcribed genes where it suppresses cryptic transcription, regulates splicing, and provides binding sites for transcription elongation factors 1. During stimulation-responsive transcription, H3.3S31 phosphorylation directly engages SETD2, facilitating rapid gene induction by ejecting the elongation corepressor ZMYND11 2. SETD2 functions as a tumor suppressor across multiple cancer types. In clear cell renal cell carcinoma (ccRCC), SETD2 mutations correlate with widespread DNA hypomethylation and aggressive disease phenotypes 3. SETD2 loss promotes ferroptosis sensitivity through H3K36me3-mediated regulation of ferrochelatase transcription and ferroptosis-related pathways 4. In pancreatic ductal adenocarcinoma, SETD2 loss unleashes BMP2 signaling via ectopic H3K27Ac gain, reshaping the tumor microenvironment toward lipid-rich cancer-associated fibroblasts that metabolically support tumor progression 5. Clinical genomic analysis identified SETD2 mutations as associated with reduced metastatic potential in immunotherapy-treated lung adenocarcinoma 6. SETD2 mutations occur recurrently in malignant pleural mesothelioma, often through gene fusions and splice alterations 7, highlighting its broad significance as a chr3-regulating tumor suppressor.