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By labeling the same molecular scaffold with different radionuclides, these agents enable seamless integration of diagnostic imaging and targeted therapy. Clinical breakthroughs with somatostatin receptor subtype 2 (SSTR2)\u2010 and prostate\u2010specific membrane antigen (PSMA)\u2010targeted radiopharmaceuticals have significantly enhanced both tumor visualization and therapeutic efficacy, establishing new benchmarks in oncology. Ongoing research is exploring novel molecular targets such as cholecystokinin\u20102 receptor (CCK2R), fibroblast activation protein (FAP), and C\u2010X\u2010C chemokine receptor type 4 (CXCR4). In parallel, there is growing interest in utilizing alternative radionuclides, including alpha\u2010particle emitters and Auger electron emitters, beyond the commonly used beta\u2010emitters, to improve therapeutic outcomes. Simultaneously, advances in ligand and linker design are being leveraged to optimize in vivo pharmacokinetics and tissue distribution. Among the emerging targets, CCK2R has attracted notable attention due to its overexpression in multiple malignancies. Research efforts have focused on improving ligand stability, receptor\u2010binding affinity, and tumor retention, while also exploring strategies to enhance CCK2R expression on cancer cells. This review offers a comprehensive overview of the current landscape in cancer radiotheranostics, exploring the role of CCK2R in cancer biology and summarizing the latest advancements in the development of CCK2R\u2010targeted radiopharmaceuticals. Using these advancements as a case study, we systematically examine key aspects of next\u2010generation radiopharmaceutical design, from target selection and ligand engineering to pharmacokinetic optimization and clinical translation, providing a multidimensional framework for future innovation in cancer radiotheranostics.<\/jats:p>","DOI":"10.1002\/cac2.70063","type":"journal-article","created":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T15:46:12Z","timestamp":1758383172000},"page":"1431-1455","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Advances in radiopharmaceuticals for cancer radiotheranostics: CCK2R targeting as a paradigm for translational innovation"],"prefix":"10.34133","volume":"45","author":[{"given":"Jing","family":"Li","sequence":"first","affiliation":[{"name":"Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"name":"Theranostics Centre of Excellence, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejun","family":"Wen","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"name":"Theranostics Centre of Excellence, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebeka Rita","family":"Reszegi","sequence":"additional","affiliation":[{"name":"Institute for Nanostructure and Solid State Physics, University of Hamburg","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemavarshini","family":"Kamalrhaj","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang J.","family":"Parak","sequence":"additional","affiliation":[{"name":"Institute for Nanostructure and Solid State Physics, University of Hamburg","place":["Hamburg, Germany"]},{"name":"Hamburg Centre for Ultrafast Imaging, University of Hamburg","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9622-0870","authenticated-orcid":false,"given":"Xiaoyuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"name":"Theranostics Centre of Excellence, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"name":"Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"name":"Clinical Imaging Research Centre, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"name":"College of Design and Engineering, National University of Singapore","place":["Singapore, Singapore"]},{"name":"National University of Singapore","place":["Singapore, Singapore"]},{"name":"National University of Singapore","place":["Singapore, Singapore"]},{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR)","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"name":"Theranostics Centre of Excellence, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"name":"Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"name":"Clinical Imaging Research Centre, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2025,9,20]]},"reference":[{"issue":"6","key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"e236","DOI":"10.1016\/S1470-2045(24)00030-5","article-title":"Recent advances and impending challenges for the radiopharmaceutical sciences in oncology","volume":"25","author":"Lapi SE","year":"2024","unstructured":"Lapi SE, Scott PJH, Scott AM, Windhorst AD, Zeglis BM, Abdel\u2010Wahab M, et\u00a0al. 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