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Transforming growth factor-\u03b2 (TGF\u03b2) induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells, with minimal expression observed in non-neoplastic tissues. We have developed a humanized monoclonal antibody, DUNP19, that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding. In multiple subcutaneous and orthotopic tumor xenograft mouse models, Lutetium-177 labeled DUNP19 ([\n                    <jats:sup>177<\/jats:sup>\n                    Lu]Lu-DUNP19) enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts, effectively halting tumor progression and prolonging survival with minimal toxicity. Transcriptomic analyses of [\n                    <jats:sup>177<\/jats:sup>\n                    Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms, including a previously reported TGF\u03b2-induced LRRC15+ signature associated with immunotherapy resistance. In a syngeneic tumor model, administration of [\n                    <jats:sup>177<\/jats:sup>\n                    Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy, yielding durable complete responses. Together, these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis, eradication, and reprogramming of LRRC15+ tumor tissue that drives immuno-resistance and disease aggressiveness in a wide range of currently untreatable malignancies.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02410-9","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T23:02:20Z","timestamp":1759186940000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0792-1569","authenticated-orcid":false,"given":"Claire 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The research reported in this manuscript was supported by Lantheus. The compound [\n                      177\n                      Lu]Lu-DUNP19 (LNTH2403) is currently undergoing preclinical evaluation for potential first-in-human use in osteosarcoma. The terms of this support have been reviewed and approved by Lantheus in accordance with its policies on research integrity and objectivity. K.H. serves as board member on Radiopharm Theranostics Scientific Advisory board. D.U. reports grants from Radiopharm Theranostics, and grants from Janssen Pharmaceuticals outside the submitted work; in addition, D.U. has a patent for EP2771688A4 issued and a patent for EP3297669A1 issued; and D.U. reports grants from Prostate Cancer Foundation and Department of Defense during the conduct of the study. Further, D.U. is a founder, consultant to and has stock in Diaprost AB; and received a speaker\u2019s honorarium from Janssen R&D LLC. D.U. and D.T. serve as board members on the Curium Scientific Advisory board. D.U. reports honoraria as a consultant to Ferring, Actithera, and Molecular Partners. K.L. reports personal fees from Sofie Biosciences outside the submitted work, and grants form Novartis, AMGEN, Mariana Oncology, Debiopharm. R.D. reports personal fees from Amgen, Panorama Medicine, and Epirium Bio outside the submitted work. D.T. reports non-financial support and other support from Diaprost during the conduct of the study; in addition, D.T. has a patent for US20220152228A1 pending and has several research project awards from the NIH, and a research project funded by Janssen Pharmaceuticals. J.C. is a founder and serves as a scientific advisor of Sofie Biosciences and Infinity Topco. He is also a founder of Trethera Therapeutics and serves as scientific advisor of Aktis Oncology. J.T.S. received honoraria as a consultant or for continuing medical education presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Immunocore, MSD, Novartis, Roche\/Genentech, and Servier. His institution received research funding from Abalos Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eisbach Bio, and Roche\/Genentech; he holds ownership in FAPI Holding (<3%); all are outside the submitted work. BAS has received travel support from Merck and honoraria from Cancer Expert Now and Curio Science. B.A.S. serves as an advisor to Merck, Pfizer, Amgen, and Johnson & Johnson; reports grants from the ASCO Conquer Cancer Foundation, the Prostate Cancer Foundation, and the Cancer Research Institute; and receives research funding from Regeneron and Amgen, all outside the submitted work. S.K.S. serves as an advisor to Apricity Health LLC, Arcus Biosciences, Baird, Boxer Capital, Bristol Myers Squibb, DAVA Oncology, Dendreon, Hervolution, Johnson & Johnson, Kahr Medical Ltd, Kiniksa Pharmaceuticals, Leerink Partners, Macrogenics, Merck, NoeticInsight, Novartis, OncLive (owned by Intellisphere LLC), Pfizer, Portage, Regeneron, Rondo Therapeutics, The Clinical Comms Group, Third Bridge, and Vicero; and receives research funding from AstraZeneca, Johnson & Johnson, and Regeneron. No disclosures were reported by the other authors.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"319"}}