MTAP loss in non-small-cell lung Cancer and beyond: Therapeutic targeting of the MAT2A-PRMT5 axis.

Abstract

Loss of methylthioadenosine phosphorylase (MTAP), which occurs in approximately 10-15% of non-small-cell lung cancers and other solid tumors, represents a key synthetic-lethal vulnerability linking tumor metabolism to epigenetic regulation. MTAP deletion disrupts the methionine salvage pathway, leading to accumulation of methylthioadenosine (MTA) and selective dependence on protein arginine methyltransferase 5 (PRMT5). This metabolic rewiring provides a unique therapeutic opportunity to target the MAT2A-PRMT5 axis. This review summarizes recent advances in understanding MTAP biology, including the PRMT5/MAT2A feedback network, tumor heterogeneity, and adaptive resistance mechanisms encompassing metabolic compensation, splicing plasticity, and immune-cold microenvironments associated with 9p21 co-deletion. Emerging clinical data on MTA-cooperative PRMT5 inhibitors and MAT2A inhibitors are discussed, alongside challenges in diagnostic accuracy, biomarker validation, and patient stratification. Despite encouraging early-phase activity, the translation of MTAP-directed therapy is constrained by diagnostic discordance, tumor adaptability, and the absence of prospective, biomarker-driven trials. Future progress will depend on harmonized detection methods, integration of metabolic biomarkers, and rational therapeutic combinations with targeted or immune-based approaches. Collectively, targeting the MTAP-MAT2A-PRMT5 axis exemplifies a metabolism-informed precision-oncology strategy with significant translational potential.