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  • Review Article
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The molecular blueprint of targeted radionuclide therapy

Nature Reviews Clinical Oncology (2025)Cite this article

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Abstract

Targeted radionuclide therapy (TRT) is a cutting-edge treatment approach in oncology that combines the molecular precision of targeted agents with the effect of radiotherapy to selectively deliver cytotoxic radiation to cancer cells. Research efforts from the past few decades have led to a diverse molecular landscape of TRT and have provided lessons for further rational development of targeted radiopharmaceuticals and expansion of the clinical applications of this treatment modality. In this Review, we discuss TRT in the context of therapeutic approaches currently available in oncology, describe the broad range of established and emerging targets for TRT including innovative approaches to exploit vulnerabilities presented by the tumour microenvironment, and address the challenges for clinical translation and molecular optimization. By bridging technological innovation and preclinical discoveries with real-world clinical implementation, ongoing research on TRT is seeking to provide effective and safe treatment options for patients across a variety of cancer types and treatment settings. Overall, we emphasize the transformative potential of TRT and highlight how a comprehensive understanding of what constitutes an optimal target can redefine clinical practice, fostering the evolution of TRT as a highly individualized and adaptable therapeutic option that improves outcomes across a broad range of cancer types.

Key points

  • Targeted radionuclide therapy (TRT) is a systemic therapeutic modality that uses ligands to tumour-associated targets to deliver radioactive payloads, leveraging molecular recognition to cause selective radiation-induced cancer cell damage while minimizing the toxicities in non-malignant tissues.

  • Increased radionuclide accessibility and advances in vector design have unlocked the potential of TRTs against a broad spectrum of tumour-associated targets, spanning pan-cancer markers that leverage tumour and microenvironmental vulnerabilities to targets confined to specific cancers.

  • Owing to advances in profiling technologies, artificial intelligence-powered tools and drug repurposing, the identification and validation of novel TRT targets is progressing at unprecedented speed.

  • Robust clinical translation requires trials that emulate real-world complexities and dynamically adapt treatments to shifting target expression, with continuous monitoring to overcome heterogeneity and resistance, while minimizing the toxicities that typically arise with conventional cancer therapies.

  • Innovations in multimerized, multitargeted, covalent-bond ligation and pretargeting strategies can improve tumour targeting while overcoming off-target and on-target off-tumour effects, and penetration barriers, expanding the potential of TRT across complex cancer landscapes.

  • Incorporating TRT early in the course of treatment and strategically selecting combination partners, such as chemotherapy, immunotherapy and targeted therapies, can help to maximize therapeutic efficacy, address resistance and enable broader oncology applications.

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Fig. 1: Clinical application of TRT in oncology.
Fig. 2: Components of targeted radionuclide therapy.
Fig. 3: Molecular targeting mechanisms in TRT.
Fig. 4: Timeline of advances and innovations in TRT molecular targeting.

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Acknowledgements

The authors thank all the peer reviewers for their constructive and valuable feedback. They also sincerely thank C. Deroose and W. Fendler for proofreading the manuscript, and S. Himmen for providing images for Fig. 1. The research of I.P. and K.T. is supported by the Accelerate.EU and Thera4Care consortiums through the Innovative Health Initiative Joint Undertaking, under Grant Agreements no. 101173001 and no. 101172788, respectively. A.T. acknowledges the support of an Emmy Noether Award from the German Research Foundation (DFG, 467788900) and the Ministry of Culture and Science of the State of North Rhine-Westphalia (NRW-Nachwuchsgruppenprogramm). A.T. acknowledges the support of an ERC starting grant (METATARGET, 101078355). A.T. holds the Peter Hans Hofschneider endowed Professorship of Molecular Medicine from the Stiftung Experimentelle Biomedizin. The research of K.H. is supported by the ILLUMINATE and Thera4Care consortiums through the Innovative Health Initiative Joint Undertaking, under Grant Agreements no. 101172722 and no. 101172788, respectively.

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Authors and Affiliations

  1. Radiobiology Unit, Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium

    Irina Primac

  2. Innovation and Translational Development Unit, Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium

    Kevin Tabury

  3. Department of Dermatology, University Hospital Essen, Essen, Germany

    Alpaslan Tasdogan

  4. German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany

    Alpaslan Tasdogan & Ken Herrmann

  5. Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium

    Sarah Baatout

  6. Department of Nuclear Medicine, University of Duisburg-Essen, University Hospital Essen, Essen, Germany

    Ken Herrmann

Authors
  1. Irina Primac
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  2. Kevin Tabury
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  3. Alpaslan Tasdogan
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  4. Sarah Baatout
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  5. Ken Herrmann
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Contributions

I.P. researched data for the article. All authors contributed substantially to discussion of the content, and wrote, reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Irina Primac.

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Competing interests

A.T. has received honoraria as a speaker from Danone and MSD. K.H. has received consultant fees from Actithera, Advanced Accelerator Applications, a Novartis company, Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien München, Janssen, Merck, Molecular Partners, MSD, NVision, Pentixapharm, Pfizer, POINT Biopharma, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, Theragnostics and Ymabs; research grants from Advanced Accelerator Applications, a Novartis company, Boston Scientific and Janssen; and has stock or other ownership interests with AdvanCell, Aktis Oncology, Convergent, NVision, Sofie Biosciences and Yellowbird Diagnostics. I.P., K.T. and S.B. declare no competing interests.

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Nature Reviews Clinical Oncology thanks R. Hicks, M. Sathekge and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Primac, I., Tabury, K., Tasdogan, A. et al. The molecular blueprint of targeted radionuclide therapy. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01069-z

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