{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T10:11:41Z","timestamp":1777803101946,"version":"3.51.4"},"reference-count":177,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016618","name":"Gilbert Family Foundation","doi-asserted-by":"crossref","award":["00005080"],"award-info":[{"award-number":["00005080"]}],"id":[{"id":"10.13039\/100016618","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Homozygous deletion of the 9p21.3 genomic locus spanning the CDKN2A\/B and MTAP genes is an event affecting 15% of cancers. While CDKN2A is a well-established tumor suppressor gene, the role of MTAP in tumorigenesis varies across cancer types. MTAP codes for methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway, and its loss has been associated with several downstream synthetic vulnerabilities. Despite multiple efforts to exploit MTAP loss for targeted therapies, none of these efforts have yielded substantial results in clinical trials. In this review, we consolidate the existing literature along with our systematic analysis to provide an updated perspective on the incidence of MTAP loss in different cancers and elucidate its impact on metabolism, immune microenvironment, and tumor progression. In addition, we summarize the therapeutic strategies that have been investigated preclinically on MTAP-null tumors before and after the advent of functional genomic screening tools. We further assess the current landscape of clinical trials investigating MTAP-targeted inhibitors, evaluating their limitations and potential avenues for improvement. The insights gained from this review will inform future research directions beyond the promising PRMT5\/MAT2A axis for rational combination therapies that would work synergistically to eradicate this devastating disease.<\/jats:p>","DOI":"10.3390\/cells14241964","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T14:22:40Z","timestamp":1765376560000},"page":"1964","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["MTAP-Null Tumors: A Comprehensive Review on Synthetic Vulnerabilities and Therapeutic Strategies"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9667-7742","authenticated-orcid":false,"given":"Bavani","family":"Subramaniam","sequence":"first","affiliation":[{"name":"Brain Tumor Institute, Center for Cancer and Immunology Research, Children\u2019s National Hospital, Washington, DC 20012, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7686-5559","authenticated-orcid":false,"given":"Wai Chin","family":"Chong","sequence":"additional","affiliation":[{"name":"Brain Tumor Institute, Center for Cancer and Immunology Research, Children\u2019s National Hospital, Washington, DC 20012, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0139-2605","authenticated-orcid":false,"given":"Aylar","family":"Babaei","sequence":"additional","affiliation":[{"name":"Brain Tumor Institute, Center for Cancer and Immunology Research, Children\u2019s National Hospital, Washington, DC 20012, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Bornhorst","sequence":"additional","affiliation":[{"name":"Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunchao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Brain Tumor Institute, Center for Cancer and Immunology Research, Children\u2019s National Hospital, Washington, DC 20012, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger","family":"Packer","sequence":"additional","affiliation":[{"name":"Brain Tumor Institute, Center for Cancer and Immunology Research, Children\u2019s National Hospital, Washington, DC 20012, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1951-9828","authenticated-orcid":false,"given":"Javad","family":"Nazarian","sequence":"additional","affiliation":[{"name":"Children\u2019s Research Center, University Children\u2019s Hospital Zurich, 8008 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/0006-291X(77)91430-9","article-title":"Methylthio group cleavage from methylthioadenosine. 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