{"title":"Targeting CAFs","authors":"Nicholas J. Bernard","doi":"10.1038/s41590-025-02248-x","DOIUrl":null,"url":null,"abstract":"<p>Cancer-associated fibroblasts (CAFs) support an immunosuppressive tumor microenvironment (TME), in part by the release of complement factors and the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor, but therapeutic targeting of these cells is a challenge. Data now published in <i>Nature</i> highlight a therapeutic strategy to avoid this outcome by reprogramming CAF metabolism using an inhibitor of nicotinamide <i>N</i>-methyltransferase (NNMT). NNMT had been previously shown to reprogram CAF biology, but the mechanisms of this effect were unclear and a highly potent inhibitor had not been developed. The researchers now validate an NNMT inhibitor from a screen of over 150,00 small molecules and show that it can alter H3K27 methylation of all CAFs and reduce tumor growth, decreasing complement activity as well as the number and function of CAFs in the TME. Importantly, the inhibitor also reduced tumor growth and metastasis in a variety of mouse models and could sensitize normally resistant tumors to immune checkpoint blockade.</p><p><b>Original reference:</b> <i>Nature</i> https://doi.org/10.1038/s41586-025-09303-5 (2025)</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"37 1","pages":""},"PeriodicalIF":27.6000,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41590-025-02248-x","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Cancer-associated fibroblasts (CAFs) support an immunosuppressive tumor microenvironment (TME), in part by the release of complement factors and the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor, but therapeutic targeting of these cells is a challenge. Data now published in Nature highlight a therapeutic strategy to avoid this outcome by reprogramming CAF metabolism using an inhibitor of nicotinamide N-methyltransferase (NNMT). NNMT had been previously shown to reprogram CAF biology, but the mechanisms of this effect were unclear and a highly potent inhibitor had not been developed. The researchers now validate an NNMT inhibitor from a screen of over 150,00 small molecules and show that it can alter H3K27 methylation of all CAFs and reduce tumor growth, decreasing complement activity as well as the number and function of CAFs in the TME. Importantly, the inhibitor also reduced tumor growth and metastasis in a variety of mouse models and could sensitize normally resistant tumors to immune checkpoint blockade.
Original reference:Nature https://doi.org/10.1038/s41586-025-09303-5 (2025)
期刊介绍：
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.
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