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While this high dependency supports rapid proliferation, it exposes a critical vulnerability: disruption of amino acid supply can specifically trigger metabolic catastrophe in cancer cells. Furthermore, tumor cells exploit this metabolic reprogramming to deplete key amino acids in the microenvironment, thereby suppressing T-cell function and facilitating immune evasion. This review systematically elucidates therapeutic strategies targeting four critical amino acid metabolic axes (glutamine, arginine, tryptophan, and methionine). We delve into how inhibition of glutamine metabolism disrupts tumor bioenergetics, how arginine deprivation selectively targets cells with synthetic defects, and how methionine restriction interferes with key epigenetic regulation. Additionally, we explore interventions for these four amino acid metabolic axes to reverse immunosuppression. Convincing preclinical and clinical evidence demonstrates that these strategies, whether as monotherapy or rational combinations with conventional treatments, exhibit significant antitumor efficacy and substantial clinical translation potential. By integrating metabolic and immunological perspectives and critically assessing translational challenges, this review aims to provide a roadmap for future development of precision combination strategies capable of overcoming drug resistance and reshaping the immune microenvironment.<\/jats:p>","DOI":"10.1007\/s00726-026-03522-4","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T05:16:33Z","timestamp":1776402993000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the amino acid metabolic axis: the Achilles\u2019 heel of tumor cells"],"prefix":"10.1007","volume":"58","author":[{"given":"Zheyu","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"issue":"10","key":"3522_CR32","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1038\/nrc.2016.71","volume":"16","author":"BJ Altman","year":"2016","unstructured":"Altman BJ, Stine ZE, Dang CV (2016) From Krebs to clinic: glutamine metabolism to cancer therapy. 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