MTAP (methylthioadenosine phosphorylase) is a metabolic enzyme that catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate, playing a crucial role in polyamine metabolism and the methionine salvage pathway. MTAP is frequently co-deleted with the tumor suppressor CDKN2A due to their proximity on chromosome 9.3, occurring in approximately 15% of all cancers 1 and up to 13% of non-small cell lung cancers 2. This deletion creates a synthetic lethal vulnerability where MTAP-deficient cancer cells become highly dependent on protein arginine methyltransferase 5 (PRMT5). When MTAP is deleted, its substrate MTA accumulates and acts as a potent and selective inhibitor of PRMT5 34. This dependency has led to the development of MTA-cooperative PRMT5 inhibitors like MRTX1719 and AMG 193, which demonstrate >70-fold selectivity for MTAP-deleted cells and show promising clinical activity with objective responses in patients with MTAP-deleted melanoma, lung cancer, and mesothelioma 56. Additionally, MTAP loss serves as a diagnostic marker for mesothelioma 7 and confers resistance to STING agonist immunotherapy by downregulating interferon regulatory factor 3 8.