Radioligand therapy in combination with CAR T cells overcomes the heterogeneous immunosuppressive prostate tumor microenvironment.

Authors

Jiangyue Liu, Iveta Fajnorova, Yuwei Ren, Kofi Poku, Shuai Yang, Yu-Hsuan Fu, Cari A Young, Lupita S Lopez, Reginaldo C A Rosa, Handan Hong, Jingting Hao, Deyi Chen, Pauline Jeanjean, Ines Camille Azrour, Ava Fakharpour, Lea Christian, John P Murad, Yukiko Yamaguchi, Laura H Porter, Vikram Adhikarla, Russell Rockne, Stephen J Forman, Yun Rose Li, Tanya B Dorff, Gail R Risbridger, Renea Taylor, Christine E Mona, Saul J Priceman

Published in

bioRxiv : the preprint server for biology. Jul 03, 2026. Epub Jul 03, 2026.

Abstract

¹⁷⁷ Lu-PSMA-617 (Pluvicto ^TM , Lu-177 RLT) is an FDA-approved targeted radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC), but its durability of response to this singular approach poses a challenge to the field. 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 ²²⁵ 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.
Combining ¹⁷⁷ 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.

PMID:
42436933
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.

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