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Revisiting the TGFβ paradox: insights from HPV-driven cancer and the DNA damage response

Nature Reviews Cancer volume 25, pages 534–544 (2025)Cite this article

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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.

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Fig. 1: TGFβ signalling is altered by HPV.
Fig. 2: TGFβ regulates DNA damage repair.
Fig. 3: Modulation of TGFβ signalling competency to promote response to genotoxic therapy and ICIs.
Fig. 4: Targeting TGFβ signalling in the βloAlthi TME can promote antitumour immune cell migration and improve response to ICIs.

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Acknowledgements

The authors acknowledge J. Gkantalis for draft figures. They also thank the research contributions of collaborators and laboratory members on which this Perspective is based. The authors also acknowledge funding from the University of California, San Francisco (UCSF) Department of Radiation Oncology, the Genentech imCORE network and National Institutes of Health (NIH) grants R01CA239235 and R01CA270332 (to M.H.B.-H.).

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Authors and Affiliations

  1. Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA

    Mary Helen Barcellos-Hoff & Sue S. Yom

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  1. Mary Helen Barcellos-Hoff
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  2. Sue S. Yom
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The authors contributed equally to the article.

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Correspondence to Mary Helen Barcellos-Hoff.

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Competing interests

M.H.B.-H. reports grants and non-financial support from Roche/Genentech; personal fees and non-financial support from Innovation Pathways, Inc.; consulting fees from Scholar Rock and Vericyte; non-financial support from Bicara during the conduct of the study; spoke at a meeting organized by for-profit Hanson-Wade in 2022 and 2023; has a patent pending for PCT/US2021/037078; and is a co-inventor on a patent pending (18/009,885) and a provisional patent (18/602,978) related to the βAlt signature owned by University of California, San Francisco (UCSF). S.S.Y. reports research support from Bristol-Myers Squibb, Merck, EMD Serono, Biomimetix and Nanobiotix.

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Nature Reviews Cancer thanks L. Wakefield, C.-H. Heldin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Barcellos-Hoff, M.H., Yom, S.S. Revisiting the TGFβ paradox: insights from HPV-driven cancer and the DNA damage response. Nat Rev Cancer 25, 534–544 (2025). https://doi.org/10.1038/s41568-025-00819-6

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