MTAP Deletion as a Therapeutic Vulnerability in Cancer: From Molecular Mechanism to Clinical Targeting

The <i>MTAP</i> (methylthioadenosine phosphorylase) gene, located on chromosome 9p21, plays a crucial role in the methionine salvage pathway and is frequently co-deleted with <i>CDKN2A</i> in various malignancies. Loss of <i>MTAP</i> expression leads to the accumulation of methylthioadenosine (MTA), which selectively inhibits protein arginine methyltransferase 5 (PRMT5) and creates a unique metabolic vulnerability in <i>MTAP</i>-deficient tumors. These alterations have emerged as promising therapeutic targets in precision oncology. Recent advances highlight the potential of exploiting <i>MTAP</i> loss through synthetic lethality approaches using PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibitors. Preclinical and early clinical data indicate that targeting these pathways can selectively impair tumor growth while sparing <i>MTAP</i>-proficient cells. Moreover, <i>MTAP</i> deletion has been associated with specific molecular and immunologic profiles that may influence treatment response and tumor microenvironment characteristics. This review summarizes current knowledge on the biological functions of <i>MTAP</i>, the mechanisms linking its loss to oncogenesis, and the evolving landscape of therapeutic strategies targeting <i>MTAP</i>-deficient cancers. Understanding these molecular dependencies offers novel opportunities for the development of precision-based therapies across diverse tumor types.