From metabolic starvation to precision therapy: engineering amino acid-targeted tumor therapeutics

Amino acid metabolism has emerged as a critical nexus linking tumor cell nutrient acquisition with immune microenvironmental regulation, providing a rich source of druggable targets for cancer therapy. Tumor cells engage in fierce metabolic competition with immune cells for key amino acids, including glutamine, arginine, tryptophan, and methionine, thereby establishing an immunosuppressive tumor microenvironment. Over the past decade, therapeutic strategies targeting this metabolic axis have evolved from preclinical proof-of-concept to active clinical development across multiple biotechnology modalities. This review provides a comprehensive overview of amino acid metabolism-targeted therapeutics, emphasizing drug development trajectories and clinical translation prospects. Enzymatic depletion strategies, tumor-selective prodrugs and the clinical development landscape of small-molecule metabolic modulators are analyzed for tumor precision therapy. Despite promising efficacy, clinical translation faces challenges including compensatory metabolic resistance, patient stratification, and the immunosuppressive dichotomy of systemic amino acid depletion. The rational integration of metabolic modulation with immune checkpoint inhibition, chemotherapy, and precision delivery systems holds promise for advancing these therapies into standard oncological practice.