The molecular blueprint of targeted radionuclide therapy.

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.