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The study reports two distinct ASCL2 expression patterns across pMMR/MSS versus dMMR/MSI-H CRCs, linking elevated ASCL2 to stemness and reduced tumor-infiltrating lymphocytes. Anti-PD-L1 coadministration enhances T-cell infiltration and antitumor regression in a mouse model. Mechanistically, ASCL2 overexpression increases TGFB, activating cancer-associated fibroblasts and driving an immune-excluded microenvironment, with improved infiltration and prognosis in Ascl2-deficient intestines, supporting ASCL2 targeting alongside ICIs for MSS CRC therapy.",{"@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/ascl2-induces-an-immune-excluded-microenvironment-by-activating-cancer-associated-fibroblasts-in-microsatellite-stable-colorectal-cancer/385145/",{"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/ascl2-induces-an-immune-excluded-microenvironment-by-activating-cancer-associated-fibroblasts-in-microsatellite-stable-colorectal-cancer/385145.png","ImageObject",300,407,{"name":92,"@type":93},"Cart","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What problem does the study address in pMMR/MSS colorectal cancer patients?","Question",{"text":113,"@type":114},"pMMR/MSS colorectal cancers are the majority yet lack sensitive responses to immune checkpoint inhibitors, prompting a need to clarify how the tumor immune microenvironment is remodeled to improve immunotherapy outcomes.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does ASCL2 expression differ between pMMR/MSS and dMMR/MSI-H CRCs?",{"text":118,"@type":114},"ASCL2 is reported to be overexpressed in pMMR/MSS CRCs, maintaining a stemness phenotype and coinciding with a lower density of tumor-infiltrating lymphocytes than in dMMR/MSI CRCs.",{"name":120,"@type":111,"acceptedAnswer":121},"What mechanism connects ASCL2 to an immune-excluded microenvironment?",{"text":122,"@type":114},"ASCL2 overexpression is associated with increased TGFB levels that stimulate activation of cancer-associated fibroblasts, thereby inducing an immune-excluded microenvironment; genetic deletion of Ascl2 reduces activated CAFs and increases infiltrating CD8+ T cells.","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},385145,1790421640,{"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":145},18829141979164,"https://eur-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Oncogene [www.nature.com/onc](www.nature.com/onc)  \nARTICLE OPEN   \nASCL2 induces an immune excluded microenvironment by activating cancer-associated fibroblasts in microsatellite stable colorectal cancer  \nDan Zhang 1,2,4, Qi-Qi Ni1,2,4, Qiao-Yan Liang 1,2, Li-Ling He1,2, Bo-Wen Qiu 1,2, Ling-Jie Zhang 1,2, Ting-Yu Mou3, Chen-Chen Le1,2, Yuan Huang 1,2, Ting-Ting Li1,2, Shu-Yang Wang1,2, Yan-Qing Ding 1,2 ✉, Hong-Li Jiao 1,2 ✉ and Ya-Ping Ye 1,2 ✉  \n© The Author(s) 2023  \n|  |  |  |\n| --- | --- | --- |\n|  | Proficient mismatch repair or microsatellite stable (pMMR/MSS) colorectal cancers (CRCs) are vastly outnumbered by deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) tumors and lack a response to immune checkpoint inhibitors (ICIs) . In this study, we reported two distinct expression patterns of ASCL2 in pMMR/MSS and dMMR/MSI-H CRCs. ASCL2 is overexpressed in pMMR/MSS CRCs and maintains a stemness phenotype, accompanied by a lower density of tumor-infiltrating lymphocytes (TILs) than those in dMMR/MSI CRCs. In addition, coadministration of anti-PD-L1 antibodies facilitated T cell infiltration and provoked strong antitumor immunity and tumor regression in the MC38/shASCL2 mouse CRC model. Furthermore, overexpression of ASCL2 was associated with increased TGFB levels, which stimulate local Cancer-associated fibroblasts (CAFs) activation, inducing an immune-excluded microenvironment. Consistently, mice with deletion of Ascl2 specifically in the intestine (Villin-Cre+, Ascl2 flox/flox, named Ascl2 CKO) revealed fewer activated CAFs and higher proportions of infiltrating CD8+ T cells; We further intercrossed Ascl2 CKO with ApcMin/+ model suggesting that Ascl2-deficient expression in intestinal represented an immune infiltrating environment associated with a good prognosis. Together, our findings indicated ASCL2 induces an immune excluded microenvironment by activating CAFs through transcriptionally activating TGFB, and targeting ASCL2 combined with ICIs could present a therapeutic |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| opportunity for MSS CRCs. |  |  |\n|  | Oncogene (2023) 42:2841–2853; [https://doi.org/10.1038/s41388-023-02806-3](https://doi.org/10.1038/s41388-023-02806-3) |  |\n|  |  |  |\n\nINTRODUCTION  \nColorectal cancers (CRCs) show high intratumoral genetic heterogeneity [1, 2], which has a major effect on the efficacy of immunotherapy. A minority (~15%) of CRCs exhibit a microsatellite instability-high (MSI-H) phenotype, a molecular indicator of defective DNA mismatch repair (MMR), and often have sustained responses to immune checkpoint inhibitors (ICIs) due to a higher density of tumor-infiltrating lymphocytes (TILs) [3, 4] . However, the majority (~85%) are microsatellite-stable (MSS) and lack sensitive responses to ICIs [5] . Therefore, elucidating the molecular mechanisms of tumor immune microenvironment remodeling to overcome the unsatisfactory immunotherapy response in patients with pMMR/MSS CRC is urgently needed.  \nAchaete-scute homolog 2 (ASCL2), a basic-helix-loop-helix transcription factor (TF), is a transcriptional target of Wnt signaling [6] . ASCL2 controls intestinal stem cell fate [7] and is also indispensable for LGR5+ basal crypt cell dedifferentiation [8] . However, the expression pattern and role of ASCL2 in intestinal tumors have been controversial. ASCL2 has been reported to be significantly upregulated in CRCs [9, 10] and promotes the proliferation, metastasis, and chemoresistance of CRC cells [11–13] . Nevertheless, Felipe et al. showed the opposite result:  \nASCL2 is silenced by CpG island methylation during CRC progression [14] . Moreover, a transgenic mouse model revealed that ectopic overexpression of ASCL2 does not increase tumor initiation or progression [15] . A new taxonomy was introduced, which identifies a consensus gene expression–based subtyping classification system for CRC into four consensus ","cbCaifQYLBpRH0Wo","https://ap.wps.com/l/cbCaifQYLBpRH0Wo","pdf",24254859,"English","# Introduction\n## Colorectal cancer immunotherapy context (pMMR/MSS vs MSI-H)\n## ASCL2 biology in Wnt signaling and intestinal stemness\n## Contradictory prior findings and rationale for this study\n## ASCL2 roles in immune regulation and immunotherapy","[{\"question\":\"What problem does the study address in pMMR/MSS colorectal cancer patients?\",\"answer\":\"pMMR/MSS colorectal cancers are the majority yet lack sensitive responses to immune checkpoint inhibitors, prompting a need to clarify how the tumor immune microenvironment is remodeled to improve immunotherapy outcomes.\"},{\"question\":\"How does ASCL2 expression differ between pMMR/MSS and dMMR/MSI-H CRCs?\",\"answer\":\"ASCL2 is reported to be overexpressed in pMMR/MSS CRCs, maintaining a stemness phenotype and coinciding with a lower density of tumor-infiltrating lymphocytes than in dMMR/MSI CRCs.\"},{\"question\":\"What mechanism connects ASCL2 to an immune-excluded microenvironment?\",\"answer\":\"ASCL2 overexpression is associated with increased TGFB levels that stimulate activation of cancer-associated fibroblasts, thereby inducing an immune-excluded microenvironment; genetic deletion of Ascl2 reduces activated CAFs and increases infiltrating CD8+ T cells.\"}]","ASCL2 induces an immune excluded microenvironment by activating cancer-associated fibroblasts in microsatellite stable colorectal cancer | PDF",1790266963,33]