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Advancing therapeutics in small-cell lung cancer

Nature Cancer volume 6, pages 938–953 (2025)Cite this article

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Abstract

Small-cell lung cancer (SCLC) accounts for 10–15% of lung cancers and is characterized by early metastasis, treatment resistance and rapid progression. Treatment advancements have been stagnant for decades, with chemotherapy as the mainstay and immune checkpoint inhibitors offering only modest survival extensions. However, new insights into tumor heterogeneity and recent practice-changing observations such as the identification of targetable cell surface proteins could effectively transform SCLC therapy. In this Review, we highlight key advances in SCLC biology, therapeutic innovation and biomarker development. Finally, we discuss the role of reverse translation in optimizing treatments, approaches to overcoming resistance and ensuring equitable access to care.

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Fig. 1: Schema integrating the current understanding of the molecular and microenvironmental complexity of SCLC.
Fig. 2: SCLC clinical course and current standard treatments.
Fig. 3: Biomarkers of ICB benefit in SCLC.
Fig. 4: Emerging therapies targeting SCLC surface proteins.
Fig. 5: Challenges and opportunities to expand the landscape of effective SCLC therapies.

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Acknowledgements

We thank N. Takahashi and P. Desai for helpful feedback on the manuscript. This work was supported by the Center for Cancer Research, the Intramural Program of the NCI (ZIA BC 011793).

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  1. Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Anish Thomas & Chirayu Mohindroo

  2. Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

    Giuseppe Giaccone

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  1. Anish Thomas
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Correspondence to Anish Thomas or Giuseppe Giaccone.

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A.T. received grants to the NCI from EMD Serono Research and Development, AstraZeneca, Gilead Sciences and ProLynx during the conduct of the study. C.M. and G.G. declare no competing interests.

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Thomas, A., Mohindroo, C. & Giaccone, G. Advancing therapeutics in small-cell lung cancer. Nat Cancer 6, 938–953 (2025). https://doi.org/10.1038/s43018-025-00996-1

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