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Chimeric antigen receptor (CAR) T cell therapy has revolutionized clinical practice for hematological malignancies, but its clinical development for solid tumors, including mCRPC, has been encumbered by antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Here, we evaluate the therapeutic combination of Lu-177 RLT and PSCA-CAR T cells to overcome these barriers. In human xenograft and mouse syngeneic prostate cancer models with homogeneous or heterogeneous antigen expression, the sequential administration of Lu-177 RLT, cyclophosphamide (Cy), and PSCA-CAR T cells improves tumor control and prolongs survival compared to monotherapies. Mechanistically, Lu-177 RLT alone or with Cy remodels the TME by promoting pro-inflammatory myeloid responses and activating endogenous T cells, while enhancing CAR T cell activation and effector function. We additionally evaluated\n                  <jats:sup>225<\/jats:sup>\n                  Ac-PSMA-617 RLT as an emerging approach in combination with CAR T cells and observed anti-tumor responses, supporting its potential as an alternative RLT partner. These findings support RLT as an immune priming strategy to enhance CAR T cell therapy and provide a rationale for clinical translation of this combination in mCRPC.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    Combining\n                    <jats:sup>177<\/jats:sup>\n                    Lu-PSMA-617 radioligand therapy with PSCA-CAR T cells improves tumor control and survival in prostate cancer models by overcoming the antigen heterogeneity and reshaping the immunosuppressive tumor microenvironment.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.02.736191","type":"posted-content","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T13:10:43Z","timestamp":1783084243000},"source":"Crossref","is-referenced-by-count":0,"title":["Radioligand therapy in combination with CAR T cells overcomes the heterogeneous immunosuppressive prostate tumor microenvironment"],"prefix":"10.64898","author":[{"given":"Jiangyue","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Medicine, Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"},{"name":"Cancer Biology and Genomics (CBG) PhD Graduate Program, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iveta","family":"Fajnorova","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Theranostics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kofi","family":"Poku","sequence":"additional","affiliation":[{"name":"Department of Radiopharmacy, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5917-2961","authenticated-orcid":false,"given":"Yu-Hsuan","family":"Fu","sequence":"additional","affiliation":[{"name":"Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cari A.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lupita S.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reginaldo C. A.","family":"Rosa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Handan","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"},{"name":"Cancer Biology and Genomics (CBG) PhD Graduate Program, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingting","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Jeanjean","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Theranostics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines Camille","family":"Azrour","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Theranostics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ava","family":"Fakharpour","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Theranostics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Christian","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Murad","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura H.","family":"Porter","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Developmental Biology, Cancer Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Adhikarla","sequence":"additional","affiliation":[{"name":"Department of Computational and Quantitative Medicine, City of Hope, 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