Unraveling the potential of targeting methionine metabolism in cancer

Methionine metabolism is a central axis of cellular homeostasis, integrating protein synthesis, redox regulation, and epigenetic control. Cancer cells exhibit a heightened dependence on methionine to sustain proliferation, primarily through enhanced flux into S-adenosylmethionine (SAM) synthesis, which fuels aberrant DNA and histone methylation and maintains oncogenic transcriptional programs. The SAM-producing enzyme methionine adenosyltransferase 2A (MAT2A) is frequently overexpressed in tumors, linking nutrient availability to epigenetic reprogramming and tumor progression. Beyond intrinsic tumor growth, dysregulated methionine metabolism reshapes the tumor microenvironment (TME) by modulating nutrient competition and impairing antitumor immunity-promoting T cell exhaustion and functional suppression. In this review, we synthesize current insights into methionine metabolism in cancer, emphasizing its roles in epigenetic plasticity, stemness, regulated cell death and metabolic crosstalk, with particularly focus on MAT2A as a metabolic vulnerability by discussing its potential for synthetic lethality-based targeting. We further evaluate methionine-restricted (MR) strategies and MAT2A inhibition as emerging interventions capable of reconditioning the TME and synergizing with immunotherapy. Finally, from a novel and integrative perspective, we map the evolving clinical landscape of methionine-targeted therapies and outline future translational directions, aiming to provide a comprehensive framework for understanding its therapeutic potential in cancer.