Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as prostate cancer due to the immunosuppressive tumor microenvironment (TME). Combining CAR T cells with existing therapies that remodel the TME and promote endogenous immune responses, such as radiation therapy and chemotherapies, may strengthen antitumor responses. Here, we assessed the potency of combining focal radiotherapy (RT), cyclophosphamide (Cy) preconditioning, and prostate stem cell antigen (PSCA)-CAR T cells against syngeneic prostate cancer models. Focal RT alone increased T cell and dendritic cell infiltration and activation in the irradiated tumor. Furthermore, the combination of all three therapies was critical for enhanced antitumor responses and survival across multiple subcutaneous, bone-metastatic, and multifocal disease models. This combination, in the irradiated TME and tumor-draining lymph nodes (tdLN), led to greater antigen presentation by myeloid cells and endogenous T cell activation and cytotoxicity. Our study demonstrates the potency of combining focal RT with PSCA-CAR T cells, significantly improving therapeutic responses in the irradiated tumor and contributing to a more robust systemic immune response against metastatic burden in prostate cancer.
bioRxiv : the preprint server for biology. 2026 Jun 24*** epublish ***
Cari A Young, Jiangyue Liu, Yuwei Ren, Reginaldo Rosa, Lea Christian, Handan Hong, Lupita Lopez, Alyssa Buckley, Jingting Hao, Yukiko Yamaguchi, Anthony K Park, Hemendra Ghimire, Amr Mohamed Hamed Abdelhamid, Darren Zuro, Susanta Hui, Catalina Martinez, Stephen J Forman, Yun Rose Li, Tanya B Dorff, John P Murad, Saul J Priceman
Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA., Cancer Biology and Genomics (CBG) PhD Graduate Program, Keck School of Medicine of USC, Los Angeles, CA 90033, USA., Department of Medicine, Division of Medical Oncology, Keck School of Medicine (KSOM) of USC, Los Angeles, CA 90033, USA., Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA., Department of Radiation Oncology, City of Hope, Duarte, CA 91010, USA., Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA.