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By coupling diagnostic imaging with therapy, in a \u201cradiotheranostic\u201d paradigm, radiopharmaceutical therapy supports patient-specific target selection, dosimetry, and on-treatment monitoring. Progress in target discovery, radioligand chemistry, and optimization of pharmacokinetics and biodistribution has improved efficacy and safety, culminating in US Food and Drug Administration approvals of [177Lu]Lu-PSMA-617 (Pluvicto) for metastatic castration-resistant prostate cancer and [177Lu]Lu-DOTA-TATE (Lutathera) for neuroendocrine tumors. These successes highlight radiopharmaceutical therapy\u2019s expanding role across oncology. This review summarizes the evolution of radiopharmaceutical therapy from early clinical milestones to modern regulatory approvals, then surveys emerging radioligands directed at new molecular pathways. We also discuss strategies to enhance therapeutic response including rational combinations with DNA damage response agents such as poly(adenosine diphosphate\u2013ribose) polymerase inhibitors or immunotherapies. Finally, we outline key challenges such as optimal patient selection, dosimetry standardization, therapeutic resistance, and access and highlight a few ways to accelerate broader clinical integration and continued innovation.<\/jats:p>","DOI":"10.1093\/jncics\/pkag056","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T11:46:09Z","timestamp":1780055169000},"source":"Crossref","is-referenced-by-count":4,"title":["Emerging role of radiopharmaceutical therapy in oncology: advances, challenges, and future directions"],"prefix":"10.1093","volume":"10","author":[{"given":"Laura","family":"Ordas","sequence":"first","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health , Madison, WI,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Foster","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health , Madison, WI,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuc","family":"Pham","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health , Madison, WI,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Ollendorff","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health , Madison, WI,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Gnanasekar","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health , Madison, WI,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Toulany","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health , Madison, WI,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9469-1388","authenticated-orcid":false,"given":"Quaovi H","family":"Sodji","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health , Madison, WI,","place":["United States"]},{"name":"Carbone Cancer Center, University of Wisconsin-Madison , Madison, WI,","place":["United States"]},{"name":"William S. 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