Clinical Evidence of Combining Radiopharmaceutical Therapy With Immune Checkpoint Inhibitors Malick Bio Idrissou, PhD; 1† Anusha Muralidhar, PhD; 2† Reinier Hernandez, PhD; 1,3,4 Quaovi H. Sodji, MD, PhD 4,5,6 * Abstract Radiopharmaceutical therapy (RPT) and immune checkpoint inhibitors (ICIs) represent transformative approaches in treating metastatic cancers. RPT uniquely delivers targeted radiation to primary and metastatic tumors, modulating the tumor microenvironment (TME) to enhance antitumor immunity. The therapeutic advantages of combining RPT with ICI have been shown preclinically. Clinical trials are now emerging, offering insights into the potential therapeutic synergy between RPT and ICI. This review highlights clinical trials of RPT combined with ICI, emphasizing their ability to improve metastatic cancer outcomes while addressing challenges such as toxicity, immunosuppressive TME, and logistical barriers, and underscores their promise to redefine cancer care. Keywords: metastatic cancer, radiopharmaceutical therapy, β-particle emitters, α-particle emitters, immune checkpoint inhibitors Introduction Metastatic disease accounts for approximately 90% of cancer-rela- ted deaths. 1-6 Unfortunately, effective therapeutic strategies remain limited despite tremendous advances in cancer research. 7 Radiopharmaceut- ical therapy (RPT) represents a groundbreaking approach to treating metastatic disease by delivering targeted radiation to tumors throughout the body. 8,9 Leveraging pharmaceuticals that selectively bind to cancer cells or accumulate through physiological mechanisms, RPT provides a precise and effective treatment modality. Remarkably, RPT has demonstrated significant therapeutic efficacy with minimal toxicity in several cancer types. 8 As the role of RPT in metastatic disease management is on the rise, its combination with immune checkpoint inhibitors (ICIs) holds the potential to enhance clinical responses beyond that achievable by either monotherapy alone. For over a century, radiation therapy, including external beam radiation therapy (EBRT) and RPT, has shown dual benefits: tumor eradication and immune activation. 10 Radiation triggers cancer cells to release damage- associated molecular patterns Affiliations: 1 Department of Medical Physics, University of Wisconsin-Madison, Madison, WI. 2 Department of Cancer Biology, University of Wisconsin-Madison, Madison, WI. 3 Department of Radiology, University of Wisconsin-Madison, Madison, WI. 4 Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI. 5 Department of Human Oncology, University of Wisconsin-Madison, Madison, WI. 6 William S. Middleton Memorial Veterans Hospital, Madison, WI. †Malick Bio Idrissou and Anusha Muralidhar contributed equally to this work Corresponding author: *Quaovi H. Sodji, MD, PhD, 600 Highland Ave, Madison, WI 53792. (qsodji@humonc.wisc.edu) Author contributions: All authors contributed to the writing, reviewing and editing of the manuscript. No artificial intelligence-assisted technology was used in the preparation of this article. Disclosures: RH: consulting fees from MonoPar Inc and Archeus technologies Inc.; Chief Technology Officer for Archeus Technologies Inc and received stocks from Archeus. All other authors have no conflicts of interest to disclose. None of the authors received outside funding for the production of this original manuscript and no part of this article has been previously published elsewhere. Funding: NIH K08 CA285941 (QHS). Published: March 1, 2025. https://doi.org/10.37549/ARO-D-24-00039 ©Anderson Publishing, Ltd. All rights reserved. Reproduction in whole or part without express written permission is strictly prohibited. 6 Applied Radiation Oncology March 2025 DETAILS ON PAGE 5