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Using molecular and spatial single-cell approaches in basal cell carcinoma, squamous cell carcinoma, and melanoma, three CAF subtypes are identified: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis shows subtype pattern shifts with increasing malignancy, including iCAF-driven immune recruitment and activation, and the potential to improve skin cancer immunotherapy by targeting CAF variants.",{"@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/cancer-associated-fibroblast-subtypes-modulate-the-tumor-immune-microenvironment-and-are-associated-with-skin-cancer-malignancy/329391/",{"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/cancer-associated-fibroblast-subtypes-modulate-the-tumor-immune-microenvironment-and-are-associated-with-skin-cancer-malignancy/329391.png","ImageObject",300,407,{"name":92,"@type":93},"Quinn","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","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 CAF subtypes are identified in the study?","Question",{"text":112,"@type":113},"The study identifies three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs).","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do CAF subtype patterns change with tumor malignancy?",{"text":117,"@type":113},"Large-cohort tissue analysis shows significant shifts in CAF subtype patterns as malignancy increases across skin cancer types.",{"name":119,"@type":110,"acceptedAnswer":120},"What role do mCAFs and iCAFs play in tumor-immune interactions?",{"text":121,"@type":113},"mCAFs are linked to extracellular matrix synthesis and may restrict T cell invasion in low-grade tumors, while iCAFs are enriched in late-stage tumors and express cytokines/chemokines that support immune cell recruitment and activation.","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},329391,1790194261,{"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":46,"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":31,"preview_page_count":4},962075114765,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Article [https://doi.org/10.1038/s41467-024-53908-9](https://doi.org/10.1038/s41467-024-53908-9)  \nCancer-associated fibroblast subtypes modulate the tumor-immune microenvironment and are associated with skin cancer malignancy  \nReceived: 10 April 2023  \n\n| Accepted: 26 October 2024 |\n| --- |\n| |\n| Check for updates |\n\nAgnes Forsthuber 1,5, Bertram Aschenbrenner 1,5, Ana Korosec1,5, Tina Jacob2, Karl Annusver 2, Natalia Krajic 1, Daria Kholodniuk1, Sophie Frech 1, Shaohua Zhu1, Kim Purkhauser 1, Katharina Lipp1, Franziska Werner3, Vy Nguyen3, Johannes Griss 3, Wolfgang Bauer 3, Ana Soler Cardona3, Benedikt Weber 1, Wolfgang Weninger3, Bernhard Gesslbauer4,  \nClement Staud4, Jakob Nedomansky4, Christine Radtke4, Stephan N. Wagner 3, Peter Petzelbauer 1, Maria Kasper 2,6  & Beate M. Lichtenberger 1,6   \nCancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers.  \nFibroblasts have been considered as rather simple structural cells, which largely contribute to extracellular matrix deposition in connective tissues and tissue repair, for a longtime. However, they present with an unprecedented plasticity and functional heterogeneity especially in pathological conditions, and exert a significant influence on different cells in their microenvironment, thus, modulating different  \nprocesses. In cancer, fibroblasts have been established as a key component of the tumor microenvironment (TME) affecting both cancer progression and the response to therapies. Fibroblast heterogeneity has been acknowledged previously as playing both tumor suppressive as well as tumor supportive roles1–7. Recent studies even demonstrated that also mutations in fibroblasts can lead to cancer8, further  \n1Skin and Endothelium Research Division, Department of Dermatology, Medical University of Vienna, Vienna, Austria. 2Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. 3Department of Dermatology, Medical University of Vienna, Vienna, Austria. 4Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria. 5These authors contributed equally: Agnes Forsthuber, Bertram Aschenbrenner, Ana Korosec. 6These authors jointly supervised this work: Maria Kasper, Beate M. Lichtenberger. [e-mail:](e-mail: maria.kasper@ki.se)[ maria.kasper@ki.se](e-mail: maria.kasper@ki.se); [beate.lichtenberger@meduniwien.ac.at](beate.lichtenberger@meduniwien.ac.at)  \nhighlighting their impact on tumorigenesis. It also has become clear that in a single tumor several fibroblast subtypes exist in parallel with different functions9. Single-cell RNA sequencing (scRNA-seq) has revealed manifold dermal fibroblast subpopulations in mouse and human healthy skin10–12. Likewise, fibroblast heterogeneity has been studied in many cancers such as breast cancer13,14, pancreatic ductaladeno carcinoma15,16, colorectal cancer17,18, head and neck squamous cell carcinoma19 and many more20. An in-depth analysis focused on fib","cbCaihOU5jeNAO5B","https://ap.wps.com/l/cbCaihOU5jeNAO5B","pdf",15959215,"English","# Study overview\n## CAF subtypes and identification\n## Shifts with increasing malignancy\n## Mechanisms of immunomodulatory CAFs\n## Implications for immunotherapy\n# Background and rationale\n## Fibroblast heterogeneity in health and disease","[{\"question\":\"What CAF subtypes are identified in the study?\",\"answer\":\"The study identifies three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs).\"},{\"question\":\"How do CAF subtype patterns change with tumor malignancy?\",\"answer\":\"Large-cohort tissue analysis shows significant shifts in CAF subtype patterns as malignancy increases across skin cancer types.\"},{\"question\":\"What role do mCAFs and iCAFs play in tumor-immune interactions?\",\"answer\":\"mCAFs are linked to extracellular matrix synthesis and may restrict T cell invasion in low-grade tumors, while iCAFs are enriched in late-stage tumors and express cytokines/chemokines that support immune cell recruitment and activation.\"}]","Cancer-associated fibroblast subtypes modulate the tumor-immune microenvironment and are associated with skin cancer malignancy | PDF",1789983995]