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Pharmacological modulation of NOTCH1 is promising for tumor immunotherapy, yet current therapies show limited effectiveness. Using data from GTEx and TCGA analyzed with multiple online bioinformatic tools, the study reveals marked heterogeneity in NOTCH1-associated immune infiltration across pan-cancer. Tumors are categorized as NOTCH1-promoted “hot” and NOTCH1-inhibited “cold,” with distinct effects on infiltration, angiogenesis-related pathways, and tsRNA function, supporting tailored immunotherapy strategies.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/the-heterogeneity-of-notch1-to-tumor-immune-infiltration-in-pan-cancer/332735/",{"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-heterogeneity-of-notch1-to-tumor-immune-infiltration-in-pan-cancer/332735.png","ImageObject",300,407,{"name":92,"@type":93},"Eden","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the study address about NOTCH1 and immunotherapy?","Question",{"text":112,"@type":113},"It addresses how NOTCH1 can act as either a tumor suppressor or promoter across cancers, creating a major challenge for immunotherapy. It specifically seeks a comprehensive view of NOTCH1-associated immune infiltration across pan-cancer.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were the pan-cancer patterns of NOTCH1-associated immune infiltration classified?",{"text":117,"@type":113},"The study found heterogeneity and divided pan-cancer into two categories: cancers where NOTCH1 promotes immune infiltration (“hot tumors”) and cancers where NOTCH1 inhibits immune infiltration (“cold tumors”).",{"name":119,"@type":110,"acceptedAnswer":120},"Which biological processes are highlighted by pathway enrichment in the two tumor categories?",{"text":121,"@type":113},"Gene ontology enrichment emphasized angiogenesis in one category and protein dealkylation in the other. Angiogenesis-related gene sets facilitated immune infiltration, while protein dealkylation-related gene sets hindered immune infiltration.","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},332735,1790168252,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"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":145,"preview_page_count":4},1374391974468,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","[www. nature.com/scientificreports](www. nature.com/scientificreports)  \nOPEN  \nThe heterogeneity of NOTCH1 to tumor immune infiltration in pancancer  \nXiaoJun Duan1,2,4, Rihan Wu3,4, Mingyang Zhang1,4, Kexin Li1, Lei Yu1, Huirong Sun1, Xingxia Hao2􀀍 & Changshan Wang1􀀍  \nNOTCH1 signaling, a vital regulator of cell proliferation and differentiation, is widely involved in the occurrence and development of malignant tumors. Pharmacological regulation of NOTCH1 is promising in tumor immunotherapy, whereas the effective rate of existing therapies remains low. NOTCH1 functions, as a cancer suppressor or a cancer promoter in different cancers, is engaged in the crosstalk between the immune microenvironment and cancer cells, posing a major challenge to immunotherapy. Therefore, a comprehensive view of the overall situation of NOTCH1-associated immune infiltration in pan-cancer should be built. The relation between NOTCH1 and immune infiltration was initially investigated in this paper. In this study, the data originated from the Genotype-Tissue Expression (GTEx) and the Cancer Genome Atlas (TCGA) databases were input  \ninto multiple online bioinformatic tools to study the characteristics of NOTCH1 in pan-cancer. We found that there was obvious heterogeneity in the NOTCH1-associated tumor immune infiltration in pan-cancer. In accordance with the heterogeneity, pan-cancer mainly fell into two categories, i.e., cancers that NOTCH1 promoted immune infiltration (termed hot tumors) and NOTCH1 inhibited immune infiltration (termed cold tumors). We further analyzed the changes of immune infiltration in pan-carcinoma species from the perspectives of NOTCH1 expression, mutation, gene function, tumor metastasis and drugs. NOTCH1 expression was significantly up-regulated in cold tumors but down-regulated in hot tumors. The Gene ontology (GO) enrichment analysis of NOTCH1 with the two categories placed stress on angiogenesis and protein dealkylation, respectively. Further, the gene sets of angiogenesis facilitated immune infiltration, whereas the gene sets of protein dealkylation hindered immune infiltration. The tsRNA associated with NOTCH1 is a type of angiogenin that potentially exertsa significant influence on angiogenesis. We have conducted a meticulous analysis of the function of this tsRNA. NOTCH1 was conducive to cancer-associated fibroblasts (CAFs) immune infiltration, while the metastatic process was more dependent on the differentiation and angiogenesis function of NOTCH1. Accordingly, the heterogeneity of NOTCH1 in immune infiltration was extensively analyzed in this study based on the pan-cancer study, which can contribute to the formulation of specific immunotherapy strategies.  \nKeywords NOTCH1, Tumor heterogeneity, Immune infiltration, Angiogenesis, tsRNA  \nNOTCH signaling refers to an ancient and conserved cellular signaling mechanism that takes on critical significance to mammalian development. NOTCH signaling regulates cell differentiation and fate by activating a conserved ligand-receptor pathway, where NOTCH1 serves as the most basic factor in the NOTCH signaling pathway. NOTCH pathways are triggered by receptor-ligand interactions since NOTCH ligands and receptors are transmembrane proteins1. NOTCH-active cells inhibit the differentiation of neighboring cells2. Under the stress of injury, NOTCH signaling pathway comprises cell differentiation and trans-differentiation in terms of the tissue to repair damage and regeneration. Thus, aberrant NOTCH signaling shows a significant correlation with aberrant repair and proliferation. NOTCH pathway activation has been identified in a broad range of human cancers (e.g., breast, colorectal, lung, pancreatic, and prostate cancers) over the past two decades3–5. Under the effect of the loss of NOTCH1, RAS activated cells were more likely to develop into squamous cell  \n1School of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia, China. 2School of Basic Science, Inner Mongoli","cbCain4dbW9UZOGV","https://ap.wps.com/l/cbCain4dbW9UZOGV","pdf",11502163,18,"English","# Introduction\n## NOTCH1 signaling and tumor biology\n## Rationale for pan-cancer immune infiltration analysis\n# Methods and Data Sources\n## GTEx and TCGA inputs\n## Bioinformatic tool-based analyses\n# Results\n## Hot vs cold tumor classification\n## Differential NOTCH1 expression and pathway enrichment\n## Links to immune infiltration mechanisms\n# Implications","[{\"question\":\"What problem does the study address about NOTCH1 and immunotherapy?\",\"answer\":\"It addresses how NOTCH1 can act as either a tumor suppressor or promoter across cancers, creating a major challenge for immunotherapy. It specifically seeks a comprehensive view of NOTCH1-associated immune infiltration across pan-cancer.\"},{\"question\":\"How were the pan-cancer patterns of NOTCH1-associated immune infiltration classified?\",\"answer\":\"The study found heterogeneity and divided pan-cancer into two categories: cancers where NOTCH1 promotes immune infiltration (“hot tumors”) and cancers where NOTCH1 inhibits immune infiltration (“cold tumors”).\"},{\"question\":\"Which biological processes are highlighted by pathway enrichment in the two tumor categories?\",\"answer\":\"Gene ontology enrichment emphasized angiogenesis in one category and protein dealkylation in the other. Angiogenesis-related gene sets facilitated immune infiltration, while protein dealkylation-related gene sets hindered immune infiltration.\"}]","The heterogeneity of NOTCH1 to tumor immune infiltration in pan-cancer | PDF",1789999271,45]