[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-352866-105":59,"doc-detail-352866-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","the-integrated-stress-response-in-cancer-mechanisms-of-tumor-adaptation-and-therapeutic-targeting","The integrated stress response in cancer - mechanisms of tumor adaptation and therapeutic targeting","","Cancer cells must continually withstand stress to proliferate and survive, and many biochemical pathways become rewired under these pressures to shape outcomes ranging from adaptation to cell death. The integrated stress response (ISR) is an evolutionarily conserved program that transiently remodels transcriptomes and translatomes in response to diverse stressors. This review explains the ISR’s pro-tumorigenic role and the upstream stress-sensing kinases that activate it by phosphorylating eIF2α.",{"@graph":69,"@context":123},[70,84,106],{"@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-integrated-stress-response-in-cancer-mechanisms-of-tumor-adaptation-and-therapeutic-targeting/352866/",{"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-integrated-stress-response-in-cancer-mechanisms-of-tumor-adaptation-and-therapeutic-targeting/352866.png","ImageObject",300,407,{"name":92,"@type":93},"Aditya","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-25","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the integrated stress response (ISR) and why is it important in cancer?","Question",{"text":113,"@type":114},"The ISR is an evolutionarily conserved mechanism that rewires transcription and translation in response to stress. Cancer cells rely on it to adapt to harsh conditions during tumor growth and metastasis.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which kinases activate the ISR and what shared target do they phosphorylate?",{"text":118,"@type":114},"Four stress-sensing kinases—PERK, GCN2, PKR, and HRI—converge on eukaryotic initiation factor 2α (eIF2α). They activate the ISR by phosphorylating the shared substrate eIF2α.",{"name":120,"@type":111,"acceptedAnswer":121},"How does eIF2α phosphorylation influence protein synthesis and cell fate?",{"text":122,"@type":114},"Phosphorylation at Ser51 suppresses global cap-dependent protein synthesis while promoting selective cap-independent translation of stress-responsive transcripts such as ATF4. ATF4-driven programs can either restore homeostasis and promote survival or trigger cell death depending on stress severity.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},352866,1790252890,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":105,"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":41},962085564549,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","Biochemical Society Transactions (2026) 54 363–374 [https://doi.org/10.1042/BST20250133](https://doi.org/10.1042/BST20250133)  \nReview Article  \nThe integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting  \n Elias Maldonado1,2 ,  Emily McIsaac1,2 and  Josie Ursini-Siegel1,2,3,4  \n1 Division of Clinical and Translational Research, McGill University, Montreal, Canada; 2 Lady Davis Institute for Medical Research, McGill University, Montreal, Canada; 3 Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada; 4 Department of Biochemistry, McGill University, Montreal, Canada  \nCorrespondence: Josie Ursini-Siegel ([giuseppina.ursini-siegel@mcgill.ca](giuseppina.ursini-siegel@mcgill.ca))  \nReceived: 23 October 2025  \nRevised: 17 February 2026  \nAccepted: 23 February 2026  \nVersion of Record published:  \n27 April 2026  \nCancer cells face continual stressors, which they must overcome to proliferate and survive in the body. Under these conditions, essential biochemical pathways are disrupted, contributing to various stress responses that either promote adaptation and survival or eventual cell death. The evolutionarily conserved integrated stress response (ISR) is a key adaptive mechanism that transiently rewires the transcriptome and translatome in response to various stressors. While the ISR is activated in healthy cells under moderate stress, cancers especially rely on this pathway to overcome harsh conditions experienced during tumor growth and metastasis. We explore the pro-tumorigenic role of the ISR, along with the upstream stress-sensing kinases that activate it. These include protein kinase R-like endoplasmic reticulum kinase, general control non-derepressible 2,  \ndouble-stranded RNA-dependent protein kinase, and heme-regulated eukaryotic translation initiation factor 2α kinase (HRI), which initiate an ISR in response to diverse stressors by phosphorylating their shared substrate, eukaryotic initiation factor-2α . An in-depth understanding of the pro-survival functions of the ISR and the contexts in which it is pro-tumorigenic is necessary to leverage the ISR as a therapeutic strategy.  \nIntroduction  \nAggressive cancers face multiple sources of cellular stress that must be overcome to establish and maintain malignancy. As tumors grow, their expanding mass often outgrows their blood supply, leading to oxygen deprivation, nutrient limitation, and difficulty meeting the energetic demands of rapidly proliferating cancer cells [1] . Cancer cells experience endoplasmic reticulum (ER) stress if they cannot maintain the energetic requirements that support increased rates of protein synthesis and folding [2,3] . The increased metabolic rate of cancer cells also increases production of reactive oxygen species (ROS), leading to oxidative stress if their antioxidant systems cannot buffer these ROS molecules [2,4] . These, among other selective pressures faced by cancer cells, activate a stress adaptation pathway called the integrated stress response (ISR) .  \nPresent in all eukaryotes, the ISR allows cells to respond to diverse stressors through the action of four stress-sensing kinases that converge upon the eukaryotic initiation factor-2α (eIF2α)asa common substrate. These include: (1) protein kinase R-like endoplasmic reticulum kinase (PERK),(2) general control non-derepressible 2 (GCN2),(3) double-stranded RNA-dependent protein kinase (PKR), and (4) heme-regulated eukaryotic translation initiation factor 2α kinase (HRI) [5–7] . eIF2α kinases are specialized to respond to a unique stress; PERK is activated during ER stress, GCN2 is activated by amino acid deficiency, PKR is activated by expression of intracellular dsRNAs or viral infection, and HRIis activated by heme depletion and mitochondrial dysfunction (Figure 1) [5–8] . These kinases  \n© 2026 The Author(s) . This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distribu","cbCaicPlYYolDKT9","https://ap.wps.com/l/cbCaicPlYYolDKT9","pdf",1498819,"English","# Introduction\n## Cellular stressors in cancer\n## ISR overview and stress-sensing kinases\n## eIF2α phosphorylation and translational control\n## ATF4-mediated fate decisions","[{\"question\":\"What is the integrated stress response (ISR) and why is it important in cancer?\",\"answer\":\"The ISR is an evolutionarily conserved mechanism that rewires transcription and translation in response to stress. Cancer cells rely on it to adapt to harsh conditions during tumor growth and metastasis.\"},{\"question\":\"Which kinases activate the ISR and what shared target do they phosphorylate?\",\"answer\":\"Four stress-sensing kinases—PERK, GCN2, PKR, and HRI—converge on eukaryotic initiation factor 2α (eIF2α). They activate the ISR by phosphorylating the shared substrate eIF2α.\"},{\"question\":\"How does eIF2α phosphorylation influence protein synthesis and cell fate?\",\"answer\":\"Phosphorylation at Ser51 suppresses global cap-dependent protein synthesis while promoting selective cap-independent translation of stress-responsive transcripts such as ATF4. ATF4-driven programs can either restore homeostasis and promote survival or trigger cell death depending on stress severity.\"}]","The integrated stress response in cancer - mechanisms of tumor adaptation and therapeutic targeting | PDF",1790101798]