{"title":"Revisiting the TGFβ paradox: insights from HPV-driven cancer and the DNA damage response","authors":"Mary Helen Barcellos-Hoff, Sue S. Yom","doi":"10.1038/s41568-025-00819-6","DOIUrl":null,"url":null,"abstract":"<p>The transforming growth factor-β (TGFβ) paradox refers to the well-established role of TGFβ in suppressing cancer in healthy tissues yet promoting malignancy in established cancers. Although this positioned TGFβ inhibitors as a potential therapeutic strategy for malignancy, therapuetic blockade has failed in multiple clinical trials. The general lack of selection principles for defining which patients would most benefit from the addition of a TGFβ inhibitor has probably hindered its deployment. Here, we highlight the therapeutic potential in TGFβ regulation of DNA repair using human papillomavirus (HPV)-driven head and neck squamous cell carcinoma (HNSCC) as an illustrative example. HPV inhibits TGFβ signalling, which in turn reduces DNA damage repair, ultimately conferring sensitivity to cancer treatments and thus contributing to the favourable prognosis of HPV-positive HNSCC. Here, we review the DNA repair deficit caused by a loss of TGFβ signalling and how this could be targeted to induce synthetic lethality. Moreover, we explore its role in predicting response to immune checkpoint inhibitors and the potential of biomarkers to select which patients with cancer could ultimately benefit from TGFβ inhibition.</p>","PeriodicalId":19055,"journal":{"name":"Nature Reviews Cancer","volume":"131 1","pages":""},"PeriodicalIF":72.5000,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Reviews Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41568-025-00819-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The transforming growth factor-β (TGFβ) paradox refers to the well-established role of TGFβ in suppressing cancer in healthy tissues yet promoting malignancy in established cancers. Although this positioned TGFβ inhibitors as a potential therapeutic strategy for malignancy, therapuetic blockade has failed in multiple clinical trials. The general lack of selection principles for defining which patients would most benefit from the addition of a TGFβ inhibitor has probably hindered its deployment. Here, we highlight the therapeutic potential in TGFβ regulation of DNA repair using human papillomavirus (HPV)-driven head and neck squamous cell carcinoma (HNSCC) as an illustrative example. HPV inhibits TGFβ signalling, which in turn reduces DNA damage repair, ultimately conferring sensitivity to cancer treatments and thus contributing to the favourable prognosis of HPV-positive HNSCC. Here, we review the DNA repair deficit caused by a loss of TGFβ signalling and how this could be targeted to induce synthetic lethality. Moreover, we explore its role in predicting response to immune checkpoint inhibitors and the potential of biomarkers to select which patients with cancer could ultimately benefit from TGFβ inhibition.
期刊介绍:
Nature Reviews Cancer, a part of the Nature Reviews portfolio of journals, aims to be the premier source of reviews and commentaries for the scientific communities it serves. The correct abbreviation for abstracting and indexing purposes is Nat. Rev. Cancer. The international standard serial numbers (ISSN) for Nature Reviews Cancer are 1474-175X (print) and 1474-1768 (online). Unlike other journals, Nature Reviews Cancer does not have an external editorial board. Instead, all editorial decisions are made by a team of full-time professional editors who are PhD-level scientists. The journal publishes Research Highlights, Comments, Reviews, and Perspectives relevant to cancer researchers, ensuring that the articles reach the widest possible audience due to their broad scope.