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  • Perspective
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Hiding in plain sight: NUT carcinoma is an unrecognized subtype of squamous cell carcinoma of the lungs and head and neck

Nature Reviews Clinical Oncology volume 22, pages 292–306 (2025)Cite this article

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Abstract

In the past two decades, treatment for non-small-cell lung cancers (NSCLCs) and head and neck squamous cell carcinoma (HNSCC) has advanced considerably, owing largely to the characterization of distinct oncological subtypes, the development of targeted therapies for each subtype and the advent of immunotherapy. Data emerging over the past two decades suggest that NUT carcinoma, a highly aggressive malignancy driven by a NUT fusion oncoprotein and arising in the lungs, head and neck, and rarely in other sites, is a squamous cell carcinoma (SCC) based on transcriptional, histopathological, cell-of-origin and molecular characteristics. NUT carcinoma has an estimated incidence of 1,400 cases per year in the United States, surpassing that of some rare NSCLC and HNSCC subtypes. However, NUT carcinoma is currently not recognized as an SCC of the lungs or head and neck. The orphan classification of NUT carcinoma as a distinct entity leads to a lack of awareness of this malignancy among oncologists and surgeons, despite early diagnosis being crucial for this cancer type with a median survival of only ~6.5 months. Consequently, NUT carcinoma is underdiagnosed and often misdiagnosed, resulting in limited research and progress in developing effective treatments in one of the most aggressive forms of lung and head and neck cancer. With a growing number of targeted agents that can potentially be used to treat NUT carcinoma, improved recognition through reclassification and inclusion of NUT carcinoma as a squamous NSCLC or an HNSCC when arising in these locations will accelerate the development of effective therapies for this disease. Thus, in the Perspective, we propose such a reclassification of NUT carcinoma as an SCC and discuss the supporting evidence.

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Fig. 1: All NUT fusion partners in NUT carcinoma are interchangeable members of the BRD4-containing NUTM1 fusion core complex.
Fig. 2: Overlapping histopathological and imaging features of NUT carcinoma and other SCCs.

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Acknowledgements

The work of J.L., G.I.S. and C.A.F. is funded by K12TR004381 (Harvard Catalyst, and the Harvard Clinical and Translational Science Center; J.L.), Lowe Center of Thoracic Oncology (J.L.), Dana–Farber Department of Medical Oncology (J.L.), R01 CA124633 (C.A.F.), U01 CA294062 (C.A.F.), R01 CA285308 (G.I.S. and C.A.F.) and R21 CA277316 (J.L., G.I.S. and C.A.F.). The Dana–Farber/Brigham and Women’s Hospital NUT Carcinoma Program receives philanthropic support from the Friends of Jay Dion Memorial Classic, the Ryan Richards Foundation, the McDevitt Strong Foundation, the Max Vincze Foundation, the Victor Family Foundation, the Alexandra Hallock Memorial Fund, and the Fortisure Foundation Fund for NUT Carcinoma.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, USA

    Jia Luo, Glenn J. Hanna & Geoffrey I. Shapiro

  2. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Jia Luo, Glenn J. Hanna & Geoffrey I. Shapiro

  3. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Justin A. Bishop

  4. Dana–Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA

    Steven G. DuBois

  5. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Lynette M. Sholl & Christopher A. French

  6. Department of Pathology, University of Virginia Medical Center, Charlottesville, VA, USA

    Edward B. Stelow

  7. Head and Neck Pathology Consultations, Woodland Hills, CA, USA

    Lester D. R. Thompson

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  1. Jia Luo
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Contributions

All authors contributed significantly to the manuscript concepts and content. J.L. and C.A.F. researched data for the article, wrote the manuscript and drafted the initial figures. J.B., S.G.D., G.J.H., L.M.S., E.B.S., L.D.R.T. and G.I.S. reviewed and edited the manuscript.

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Correspondence to Jia Luo or Christopher A. French.

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Competing interests

J.L. reports honoraria from Cancer GRACE, Community Cancer Education Inc., Physicians’ Education Resource, Targeted Oncology and VJ Oncology; advisory board participation for Amgen, Astellas and AstraZeneca; institutional research support from Erasca, Genentech, Kronos Bio, Novartis and Revolution Medicines; and personal fees from Blueprint Medicines, Daiichi Sankyo and Erasca. A patent filed by Memorial Sloan Kettering Cancer Center related to multimodal features to predict response to immunotherapy (PCT/US2023/115872) is pending. G.J.H. reports grants or contracts from ACCRF, Actuate Therapeutics, ASCO CCF, Bicara, Bristol Myers Squibb, Elevar Therapeutics, Exicure, Gateway for Cancer Research, Genentech, GSK, ImmunityBio, Kartos, Kite (a Gilead company), KSQ Therapeutics, Kura Oncology, Regeneron, Repertoire, Sanofi Genzyme, Secura Bio and V Foundation; and advisory roles for and/or honoraria from Bicara, Bio-Rad, Boxer Capital, Bristol Myers Squibb, Coherus, Elevar, Exicure, General Catalyst, Guardian Bio, KSQ Therapeutics, Kura Oncology, Massachusetts Medical Society, Merck, Naveris, Nextech, Prelude, Rain, Regeneron, Remix, Replimune, Sanofi Genzyme, SIRPant and Surface Oncology. S.G.D. reports honoraria from and/or advisory board participation for Amgen, Bayer, InhibRx and Jazz Pharmaceuticals; and travel expenses from LOXO Oncology, Roche and Salarius. G.I.S. reports personal fees from Artios, Bayer, Bicycle Therapeutics, Blueprint Medicines, Boehringer Ingelheim, Concarlo Holdings, Cybrexa Therapeutics, CytomX Therapeutics, ImmunoMet, Janssen, Kymera Therapeutics, Merck KGaA/EMD-Serono, Syros, Xinthera and Zentalis; grants from Bristol Myers Squibb, Eli Lilly, Merck KGaA/EMD-Serono, Pfizer and Tango; has a patent for “Dosage regimen for sapacitabine and seliciclib”, issued to Cyclacel Pharmaceuticals and G.I.S., and a patent for “Compositions and methods for predicting response and resistance to CDK4/6 inhibition”, issued to Liam Cornell and G.I.S. C.A.F. reports research funding and consultancy fees from Boehringer Ingelheim.

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Luo, J., Bishop, J.A., DuBois, S.G. et al. Hiding in plain sight: NUT carcinoma is an unrecognized subtype of squamous cell carcinoma of the lungs and head and neck. Nat Rev Clin Oncol 22, 292–306 (2025). https://doi.org/10.1038/s41571-025-00986-3

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