Recent advances in pretargeting strategies for cancer nuclear imaging and radionuclide therapy.

Pretargeting strategies, which decouple the delivery of the targeting vector from the injection of the radioactive ligand, represent a major advancement in cancer nuclear imaging and radionuclide therapy. This approach effectively overcomes the high background signal and radiotoxicity associated with traditional direct targeting methods, which arise from the slow clearance of the carriers. This review systematically summarizes recent advances in pretargeting technologies for cancer. First, we provide a detailed comparison of noncovalent pretargeting strategies and bioorthogonal reaction-based covalent pretargeting strategies. Subsequently, various targeting vectors used in bioorthogonal nuclear imaging, such as antibodies, peptides, nanoparticles, and cell surface engineering are reviewed, and the potential of pretargeting strategies to enhance the efficacy of radionuclide therapy is discussed. Furthermore, the current status of clinical translation is outlined, together with the major challenges related to reaction kinetics, in vivo stability, and immunogenicity. Finally, future perspectives are presented, emphasizing the critical role of multidisciplinary integration among chemistry, materials science, biology, and clinical medicine in advancing the clinical application of pretargeting strategies.