Methionine restriction for cancer therapy: From preclinical studies to clinical trials

Methionine restriction (MR) has shown significant promise in cancer therapy because it targets the unique methionine dependency of many tumors. However, despite extensive research on MR, a clear synthesis of preclinical findings and their translation into clinical settings is lacking. This review aims to address this gap by consolidating existing evidence, identifying challenges, and highlighting opportunities for advancing MR as a viable cancer treatment strategy. Preclinical studies have revealed that MR effectively hinders cancer cell proliferation, triggers cell cycle arrest, and enhances the effectiveness of standard treatments, including chemotherapy and radiotherapy. Mechanistically, MR disrupts critical cancer pathways by influencing epigenetic regulation, redox balance, and autophagy. Moreover, animal models have demonstrated notable tumor suppression and extended survival, underscoring the therapeutic potential of MR. Early-phase clinical trials are now examining MR in combination with established therapies, reporting positive preliminary results regarding safety and tolerability, and investigating biomarkers for predicting patient responsiveness. These findings suggest the utility of MR as a complementary treatment strategy, particularly for tumors resistant to conventional therapies. The outcomes of this study underscore the importance of further research to refine MR protocols, understand long-term effects, and identify optimal patient groups. Furthermore, combining MR with immunotherapies, targeted treatments, and advanced modalities such as chimeric antigen receptor (CAR)-T cell therapy may offer new therapeutic pathways. Additionally, the development of MR-mimetic drugs and targeted supplements can improve patient compliance and broaden the therapeutic applicability of MR. Large-scale clinical trials are essential to evaluate the efficacy of MR across diverse cancer types, focusing on sustainability and safety over extended periods. If successful, MR can transform cancer therapy by exploiting metabolic vulnerabilities in cancer cells, providing a novel and less toxic treatment option for challenging malignancies.