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Translating premalignant biology to accelerate non-small-cell lung cancer interception

Nature Reviews Cancer volume 25, pages 379–392 (2025)Cite this article

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Abstract

Over the past decade, substantial progress has been made in the development of targeted and immune-based therapies for patients with advanced non-small-cell lung cancer. To further improve outcomes for patients with lung cancer, identifying and intercepting disease at the earliest and most curable stages are crucial next steps. With the recent implementation of low-dose computed tomography scan screening in populations at high risk, there is an emerging unmet need for new diagnostic, prognostic and therapeutic tools to help treat patients suspected of harbouring premalignant lesions and minimally invasive non-small-cell lung cancer. Continued advances in the identification of the earliest drivers of lung carcinogenesis are poised to address these unmet needs. Employing multimodal approaches to chart the temporal and spatial maps of the molecular events driving lung premalignant lesion progression will refine our understanding of early carcinogenesis. Elucidating the molecular drivers of premalignancy is critical to the development of biomarkers to detect those incubating a premalignant lesion, to stratify risk for progression to invasive cancer and to identify novel therapeutic targets to intercept that process. In this Review, we summarize emerging insights into the earliest cellular and molecular events associated with lung squamous and adenocarcinoma carcinogenesis and highlight the growing opportunity for translating these insights into clinical tools for early detection and disease interception to transform the outcomes for those at risk for lung cancer.

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Fig. 1: Field-level alterations in the airway and lung.
Fig. 2: Cellular and molecular alterations in pre-invasive and early-stage LUSC.
Fig. 3: Cellular and molecular alterations in pre-invasive and early-stage lung adenocarcinoma.

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Acknowledgements

Investigators supported by in part by: the National Cancer Institute (NCI) Human Tumour Atlas Network (HTAN) (U2CCA233238-01) (A.E.S., S.M.D., S.A.M., H.K., S.M.J.); Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Cancer Research Grant (grant number: SU2C-AACR-DT23-17 to S.M.D. and A.E.S.). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C.

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Authors and Affiliations

  1. Sectional Computational Biomedicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

    Sarah A. Mazzilli & Avrum E. Spira

  2. Division of Pathology-Lab Medicine, Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA

    Zahraa Rahal & Humam Kadara

  3. Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK

    Maral J. Rouhani & Sam M. Janes

  4. Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, and Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    Steven M. Dubinett

  5. Johnson & Johnson Innovative Medicine, Boston, MA, USA

    Avrum E. Spira

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Contributions

S.A.M., A.E.S., Z.R., M.J.R. and S.M.D. researched data for the article. S.A.M., A.E.S., S.M.J., H.K. and S.M.D. contributed substantially to discussion of the content. S.A.M., A.E.S., Z.R., M.J.R. and S.M.D. wrote the article. S.A.M., A.E.S., Z.R., S.M.J., H.K. and S.M.D. reviewed and/or edited the manuscript before submission.

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Correspondence to Sarah A. Mazzilli or Avrum E. Spira.

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Competing interests

A.E.S. is an employee of Johnson and Johnson Innovative Medicine. S.A.M., S.M.D. and H.K. have sponsor research agreements with Johnson and Johnson supporting research in the area. The remaining authors declare no competing interests.

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Nature Reviews Cancer thanks Kathryn O’Donnell, Tae Min Kim and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Bronchoscopy

A clinical endoscopic technique using a tube with a light and camera to visualize the bronchial airways.

Ground-glass opacities

(GGOs). Light, hazy areas of increased opacity that appear on LDCT images.

Immune cold

Tissue that lacks immune infiltration154.

Immune hot

Tissue with abundant immune infiltration154.

Low-dose computed tomography

(LDCT). Medical imaging technique that is employed for lung cancer screening and uses a low-dose x-ray to take serial images of the chest to create a 3D rendering.

Precancerous, premalignant, preneoplastic and pre-invasive lesions

Histopathological changes to the normal tissue architecture driven by genomic, transcriptional and epigenetic changes that suggest progression towards carcinoma but have the capacity to naturally resolve.

Social determinants of health

Non-medical factors that influence health outcomes, including the conditions in the environments where people are born, live, work, worship and age, that are impacted by policy, income and access to health care155.

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Mazzilli, S.A., Rahal, Z., Rouhani, M.J. et al. Translating premalignant biology to accelerate non-small-cell lung cancer interception. Nat Rev Cancer 25, 379–392 (2025). https://doi.org/10.1038/s41568-025-00791-1

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