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Loss of MTAP disrupts methylthioadenosine phosphorylase activity and has been linked to multiple downstream synthetic vulnerabilities, yet prior targeted approaches have produced limited clinical-trial impact. This review consolidates incidence data, analyzes metabolic and immune microenvironment effects, and summarizes preclinical and clinical MTAP-targeted strategies, highlighting limitations and opportunities for improved combinations beyond the PRMT5/MAT2A axis.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/mtap-null-tumors-a-comprehensive-review-on-synthetic-vulnerabilities-and-therapeutic-strategies/374935/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/mtap-null-tumors-a-comprehensive-review-on-synthetic-vulnerabilities-and-therapeutic-strategies/374935.png","ImageObject",300,407,{"name":92,"@type":93},"RuangKosong","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What genetic event defines MTAP-null tumors?","Question",{"text":112,"@type":113},"MTAP-null tumors are characterized by homozygous deletion of the 9p21.3 genomic locus spanning CDKN2A/B and MTAP, which also disrupts MTAP function.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Why is MTAP loss considered a therapeutic opportunity?",{"text":117,"@type":113},"MTAP loss impairs the methionine salvage pathway, triggering downstream metabolic vulnerabilities that can be exploited for targeted therapies.",{"name":119,"@type":110,"acceptedAnswer":120},"Have MTAP-targeted therapies succeeded in clinical trials so far?",{"text":121,"@type":113},"Despite many preclinical efforts, the review states that existing MTAP-loss exploitation strategies have not produced substantial results in clinical trials.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},374935,1790822286,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":41,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},962090883219,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Review  \nMTAP-Null Tumors: A Comprehensive Review on Synthetic Vulnerabilities and Therapeutic Strategies  \nBavani Subramaniam 1, Wai Chin Chong 1, Aylar Babaei 1, Miriam Bornhorst 2, Chunchao Zhang 1, Roger Packer 1 and Javad Nazarian 3, *  \nAcademic Editor: Edward V. Prochownik  \nReceived: 9 October 2025  \nRevised: 1 December 2025  \nAccepted: 8 December 2025  \nPublished: 10 December 2025  \nCitation: Subramaniam, B.; Chong, W.C.; Babaei, A.; Bornhorst, M.; Zhang, C.; Packer, R.; Nazarian, J. MTAP-Null Tumors: A Comprehensive Review on Synthetic Vulnerabilities and Therapeutic Strategies. Cells 2025, 14, 1964. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells14241964  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/lice](https://creativecommons.org/lice)[nses/by/4.0/](nses/by/4.0/)) .  \n1 Brain Tumor Institute, Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC 20012, USA; [bsubramani@childrensnational.org](bsubramani@childrensnational.org) (B.S.)  \n2 Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA  \n3 Children’s Research Center, University Children’s Hospital Zurich, 8008 Zurich, Switzerland  \n* [Correspondence: javad.nazarian@kispi.uzh.ch](Correspondence: javad.nazarian@kispi.uzh.ch)  \nAbstract  \nHomozygous 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.  \nKeywords: methylthioadenosine phosphorylase; CDKN2A; cancer; metabolism; therapy  \n1. Introduction  \nThe discovery of the methylthioadenosine phosphorylase (MTAP) enzyme in malignant murine hematopoietic cells in 1977 was a significant scientific milestone that laid the groundwork for future targeted therapies [1] . MTAP was found to be absent in certain cancer cells that also showed increased dependency on methylthio groups for cell division, thus establishing its role as an important metabolic enzyme [2] . Over the years, several other human cancers including leukemias and solid tumors showed absence of MTAP, prompting researchers to dive deeper into comprehending its role in oncogenesis [3,4] . In 1984, using mouse-human somatic cell hybridization, the location of the MTAP gene was assigned to human chromosome 9, specifically between the regions 9p and 9q [5] . A decade later, the cyclin-dependent kinase 2A (CDKN2A) gene was identified at the 9p21 region, which is homozygously deleted in multiple cancers [6] . In rece","cbCaiiOvX9Lj5lnP","https://ap.wps.com/l/cbCaiiOvX9Lj5lnP","pdf",1525144,"English","# Introduction\n# Loss of MTAP and Disease Overview\n## A Versatile Biomarker for Targeted Therapy","[{\"question\":\"What genetic event defines MTAP-null tumors?\",\"answer\":\"MTAP-null tumors are characterized by homozygous deletion of the 9p21.3 genomic locus spanning CDKN2A/B and MTAP, which also disrupts MTAP function.\"},{\"question\":\"Why is MTAP loss considered a therapeutic opportunity?\",\"answer\":\"MTAP loss impairs the methionine salvage pathway, triggering downstream metabolic vulnerabilities that can be exploited for targeted therapies.\"},{\"question\":\"Have MTAP-targeted therapies succeeded in clinical trials so far?\",\"answer\":\"Despite many preclinical efforts, the review states that existing MTAP-loss exploitation strategies have not produced substantial results in clinical trials.\"}]","MTAP-Null Tumors - A Comprehensive Review on Synthetic Vulnerabilities and Therapeutic Strategies | PDF",1790202800,76]