{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:15:15Z","timestamp":1785413715480,"version":"3.56.0"},"reference-count":144,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n of Spain","doi-asserted-by":"crossref","award":["PID20221403880B-I00"],"award-info":[{"award-number":["PID20221403880B-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"crossref"}]},{"award":["PID20221403880B-I00"],"award-info":[{"award-number":["PID20221403880B-I00"]}],"id":[{"id":"https:\/\/ror.org\/05r0vyz12","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Personalized oncology seeks to selectively block specific dysregulated pathways to arrest cancer development. Increased glutamine metabolism is a hallmark of cancer, and 6-diazo-5-oxo-L-norleucine (DON), a structural analog of L-glutamine, was the first compound used to target the exacerbated nitrogen metabolism observed in cancer cells. However, its clinical application was limited by unacceptable toxicity. With the same goal of blocking glutamine metabolism, several specific glutaminase inhibitors have been characterized in recent decades, showing promising antitumor activity. Nevertheless, this strategy frequently induces adaptive metabolic resistance that must be counteracted. In this context, glutaminase has become a key target in combination therapies for several tumor types aimed at restricting anabolic adaptation when single metabolic therapy fails, emerging as a possible synergistic therapeutic intervention. Consequently, combination therapies that include glutaminase inhibition alongside additional agents to counteract the metabolic plasticity of cancer have emerged as a promising approach in personalized antitumor pharmacology. This review provides a historical-to-translational overview of glutamine-targeted therapies, with particular emphasis on glutaminase inhibitors, including compound 968, BPTES, CB-839, and next-generation inhibitors, as well as DON-derived prodrugs. We discuss their mechanisms of action and their integration with chemotherapy, targeted therapies, radiotherapy, and immunotherapy, highlighting how glutamine metabolism targeting influences tumor metabolic adaptation, redox homeostasis, therapy resistance, and tumor\u2013immune interactions. Finally, we examine current clinical developments, emerging therapeutic combinations, and the challenges that must be addressed for the incorporation of glutamine metabolism targeting into precision oncology.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070850","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T02:34:44Z","timestamp":1783996484000},"page":"850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["70 Years of DON and Beyond: Glutaminase Inhibition as a Synergistic Strategy in Cancer Combination Therapy"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2457-9884","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"Campos-Sandoval","sequence":"first","affiliation":[{"name":"Canceromics Lab, Departamento de Biolog\u00eda Molecular y Bioqu\u00edmica, Universidad de M\u00e1laga, 29071 M\u00e1laga, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA-Plataforma BIONAND), Universidad de M\u00e1laga, 29071 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"De los Santos-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Canceromics Lab, Departamento de Biolog\u00eda Molecular y Bioqu\u00edmica, Universidad de M\u00e1laga, 29071 M\u00e1laga, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA-Plataforma BIONAND), Universidad de M\u00e1laga, 29071 M\u00e1laga, Spain"},{"name":"Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain"},{"name":"Centre for Genomics and Oncological Research Pfizer (GENYO), University of Granada, Andalusian Regional Government, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3317-3963","authenticated-orcid":false,"given":"Javier","family":"M\u00e1rquez","sequence":"additional","affiliation":[{"name":"Canceromics Lab, Departamento de Biolog\u00eda Molecular y Bioqu\u00edmica, Universidad de M\u00e1laga, 29071 M\u00e1laga, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA-Plataforma BIONAND), Universidad de M\u00e1laga, 29071 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9795-1993","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Mat\u00e9s","sequence":"additional","affiliation":[{"name":"Canceromics Lab, Departamento de Biolog\u00eda Molecular y Bioqu\u00edmica, Universidad de M\u00e1laga, 29071 M\u00e1laga, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA-Plataforma BIONAND), Universidad de M\u00e1laga, 29071 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/nrc.2016.71","article-title":"From Krebs to clinic: Glutamine metabolism to cancer therapy","volume":"16","author":"Altman","year":"2016","journal-title":"Nat. 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