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This reprogramming can generate metabolic vulnerabilities that are preferential to cancer cells, positioning cancer metabolism as a promising therapeutic target. Folate antimetabolites since the 1940s led to many strategies, and recent metabolome-focused technologies enable more targeted agents. However, many new drugs underperform as monotherapies, while mechanism-driven combination regimens show better clinical promise, including approaches centered on amino acid, fatty acid, and glucose metabolism.",{"@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/the-landscape-of-cancer-metabolism-as-a-therapeutic-target-review-article/374728/",{"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/the-landscape-of-cancer-metabolism-as-a-therapeutic-target-review-article/374728.png","ImageObject",300,407,{"name":92,"@type":93},"eBook King","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-24","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why does cancer metabolism become a therapeutic target?","Question",{"text":112,"@type":113},"Cancer progression drives metabolic reprogramming to adapt to nutrient, oxygen, and acidity differences in the tumor microenvironment. This adaptation creates metabolic vulnerabilities that can be unique to cancer cells.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What limits many cancer metabolism drugs when used as monotherapies?",{"text":117,"@type":113},"Newer and earlier agents often do not show sufficient efficacy in clinical trials as single agents, reflecting that targeting metabolism alone may be insufficient.",{"name":119,"@type":110,"acceptedAnswer":120},"How do combination therapies improve therapeutic outcomes?",{"text":121,"@type":113},"Combination regimens are designed from precise mechanistic insights and can incorporate agents such as immune-checkpoint and signaling-pathway inhibitors. Such strategies have shown promising efficacy compared with monotherapies.","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},374728,1790398364,{"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":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36},962088006270,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","Pathology International  \nREVIEW ARTICLE   \nThe Landscape of Cancer Metabolism as a Therapeutic Target  \nKenji Ohshima   \nDepartment of Molecular Pathology, Faculty of Medicine, Hyogo Medical University, Nishinomiya, Japan Correspondence: Kenji Ohshima ([ke-ohshima@hyo-med.ac.jp](ke-ohshima@hyo-med.ac.jp))  \nReceived: 1 April 2025 | Revised: 12 April 2025 | Accepted: 13 June 2025  \nKeywords: amino acid metabolism | cancer metabolism | cancer therapy | combination therapy | fatty acid metabolism | glucose metabolism  \nABSTRACT  \nCancer cells reprogram their metabolism during progression to adapt to the tumor microenvironment, which is characterized by distinct differences in nutrient availability, oxygen concentrations, and acidity. This metabolic reprogramming can simultaneously create metabolic vulnerabilities unique to cancer cells, making cancer metabolism a promising therapeutic target. Since the clinical application of folate antimetabolites in the 1940s, numerous therapeutic strategies targeting cancer metabolism have been developed. In recent years, advancements in technologies such as metabolome analysis have facilitated the development of agents that more specifically target cancer cell metabolism. However, these newly developed agents often face challenges in demonstrating efficacy as monotherapies in clinical trials. Nevertheless, combination therapies, designed based on precise mechanistic insights and incorporating agents such as immune‐checkpoint and signaling‐pathway inhibitors, have shown promising efficacy. This review provides an overview of the current landscape of therapeutic strategies targeting cancer metabolism, with a particular focus on approaches targeting amino acid, fatty acid, and glucose metabolism in cancer cells.  \n1 | Introduction  \nMetabolic reprogramming has been recognized as one of the hallmarks of cancer [1–3] . Numerous studies have demonstrated that cancer cells undergo metabolic alterations during initiation and progression [4] . As tumors advance, cancer cells encounter and adapt to various metabolic stresses within the acidic and hypoxic tumor microenvironment, which has a distinct nutrient composition compared with normal tissues. These metabolic adaptations during tumor progression simultaneously create metabolic vulnerabilities unique to cancer cells, making them potential therapeutic targets.  \nTherapeutic strategies targeting cancer metabolism represent one of the most established research fields. As early as the 1940s, pediatric pathologist Sidney Farber reported the efficacy of a folate metabolism antagonist in patients with leukemia [5] . Following this discovery, anti‐metabolite drugs, such as the purine analog 6‐mercaptopurine, the pyrimidine analog 5‐fluorouracil (5‐FU), and gemcitabine, were developed, many of which remain in clinical use today. However, these agents are not specific to cancer cell metabolism and can cause damage to normal cells.  \nIn recent years, advancements in technologies such as metabolome analysis and mass spectrometry imaging have identified  \n\n| Abbreviations: 5‐FU, 5‐fluorouracil; ACC, acetyl‐CoA carboxylase; ACLY, ATP‐citrate lyase; ACSS2, acetyl‐CoA synthetase 2; ADI‐PEG20, pegylated arginine deiminase; ADSL, adenylosuccinate lyase; AHCY, adenosylhomocysteinase; AML, acute myeloid leukemia; ARG, arginase; ASL, argininosuccinate lyase; ASNS, asparagine synthetase; ASS1, argininosuccinate synthetase 1; cGAS, cyclic GMP‐AMP synthase; CoA, coenzyme A; cPLA2, cytosolic phospholipase A2; DON, 6‐diazo‐5‐oxo‐L‐norleucine; ENO, enolase; ERK, extracellular signal‐regulated kinase; FASN, fatty acid synthase; FLT3‐ITD, internal tandem duplication of the FMS‐like tyrosine kinase 3 gene; GCN2, general control nonderepressible 2; GLS1, glutaminase1; GLUT, glucose transporter; MAT2A, methionine adenosyltransferase 2 A; MS, methionine synthase; MTA, methylthioadenosine; MTAP, methylthioadenosine phosphorylase; MTDIA, methylthio‐DADMe‐immucillin‐A; mTORC1, mecha","cbCaiqLdglAG5etl","https://ap.wps.com/l/cbCaiqLdglAG5etl","pdf",1981423,16,"English","# Introduction\n# Therapeutic strategies targeting cancer metabolism\n# Metabolic vulnerabilities and technological advances\n# Combination therapy rationale","[{\"question\":\"Why does cancer metabolism become a therapeutic target?\",\"answer\":\"Cancer progression drives metabolic reprogramming to adapt to nutrient, oxygen, and acidity differences in the tumor microenvironment. This adaptation creates metabolic vulnerabilities that can be unique to cancer cells.\"},{\"question\":\"What limits many cancer metabolism drugs when used as monotherapies?\",\"answer\":\"Newer and earlier agents often do not show sufficient efficacy in clinical trials as single agents, reflecting that targeting metabolism alone may be insufficient.\"},{\"question\":\"How do combination therapies improve therapeutic outcomes?\",\"answer\":\"Combination regimens are designed from precise mechanistic insights and can incorporate agents such as immune-checkpoint and signaling-pathway inhibitors. Such strategies have shown promising efficacy compared with monotherapies.\"}]","The Landscape of Cancer Metabolism as a Therapeutic Target - Review Article | PDF",1790202271]