A radiopharmaceutical enhances CAR T cells against radio-sensitive and radio-resistant neuroblastoma by tumor sensitization and TME remodeling

作者：Constanza Rodríguez, Robert S. Edinger, George Diehl, Jeyshka M. Reyes‐González, Woonghee Lee, John Buckley, Jangsuk Oh, Divya Nambiar, K E Baidoo, Reona Okada, Ira Phadke, Zoe Schmiechen, Hannah Khan, Yash Sakhalkar, Angel Cortez, Anders Josefsson, Jessie R. Nedrow, Ayla White, Deborah E. Citrin, Xiyuan Zhang, Carolyn J. Anderson, Freddy E. Escorcia, Ravi B. Patel, Rosa Nguyen · 发表于：Cell Reports Medicine · 年份：2026 · DOI：10.1016/j.xcrm.2026.102884 · 研究领域：CAR-T cell therapy research、Neuroblastoma Research and Treatments、Virus-based gene therapy research

Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as neuroblastoma (NB). Key obstacles include extensive tumor burden and the presence of an immunosuppressive tumor microenvironment (TME). We employ targeted radiopharmaceutical therapy (RPT) using [ 67 Cu]Cu-LLP2A and show that it potentiated the anti-tumor activity of CAR T cells in radio-sensitive and radio-resistant NB models via distinct mechanisms. In radio-sensitive NB, RPT is directly tumoricidal while also enhancing CAR T cell efficacy through pro-immune pathways, most notably via the TNF-α pathway, leading to paracrine activation of T cells. In radio-resistant NB, RPT improves CAR T cells by remodeling the myeloid compartment in the TME and increasing the formation of immunological niches of cytotoxic CD8 + GZMB + and CD4 + GZMB + CAR T cells. While neither treatment modality alone can effectively treat NB, the combination of VLA-4-targeted RPT and GD2 or B7-H3 CAR T cells augments anti-tumor efficacy, resulting in marked tumor regression in preclinical NB models.