Role of methionine metabolism in cancer: recent advances in molecular mechanisms and therapeutic implications

Methionine is essential for protein synthesis and serves as a precursor to S-adenosylmethionine, supporting epigenetic modifications and cell growth. Unlike normal cells, cancer cells are dependent on methionine. Therapeutic strategies targeting metabolic vulnerability show promise but face challenges related to tumor heterogeneity and adaptive resistance, limiting clinical translation. This review comprehensively explores methionine metabolism in cancer, detailing its uptake, transport, and metabolic pathways that underpin tumor development. We examine tumor dependency on methionine across various cancer types and subtypes, highlighting oncogene-driven variability, including the pivotal roles of methionine adenosyltransferases (MATs), the methionine salvage enzyme 5’-methylthioadenosine phosphorylase (MTAP), and polyamine synthesis enzymes such as ornithine decarboxylase (ODC) and adenosylmethionine decarboxylase 1 (AMD1). Epigenetic contributions involving DNA, RNA, and histone methylation are discussed, emphasizing their tissue-specific implications, such as the MATI/III:MATII ratio in liver cancer and methionine metabolic features in glioblastoma, including PET imaging applications. This review further addresses methionine metabolic plasticity within the tumor microenvironment, focusing on epigenetic and immune reprogramming, metabolic checkpoint regulation, and the role of methionine in tumor-initiating cells and cancer stem cells. Therapeutic strategies targeting methionine dependence, including dietary restriction, methioninase enzyme therapies, transporter inhibition, and combination regimens aimed at enhancing efficacy, are critically evaluated. Finally, we discuss current challenges and future directions, emphasizing the need for tumor-selective interventions, improved delivery systems, and personalized metabolic diagnostics to translate metabolic vulnerabilities into effective clinical cancer therapies. This integrated analysis underscores the potential of targeting methionine metabolism for advancing cancer treatment strategies.