Tumor Microenvironmental Regulation of CAR T-Cell Therapy in High Risk Medulloblastoma.
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BACKGROUND: B7-H3-directed chimeric antigen receptor (CAR) T cell therapy has demonstrated clinical safety and antitumor activity in pediatric brain tumors (pBTs) but lacks durable responses. Although preclinical studies show efficacy, the CAR designs that best support sustained function in immunosuppressive tumor microenvironments (TMEs) remain unclear. Group 3 medulloblastoma (G3MB) is a lethal pBT with poor responsiveness to immunotherapy. Within the TME, myeloid cells dominate the immune landscape and regulate T cell function through innate immune pathways, including the Toll-like receptor 7/8 (TLR7/8) axis. While TLR7/8 agonists activate antitumor myeloid programs, their integration with CAR T-cell therapy has not been explored. Therefore, we hypothesize that CAR architecture and TLR7/8-mediated myeloid activation cooperatively govern CAR T-cell function and subsequent therapeutic outcomes in G3MB. METHODS: B7-H3 CARs incorporating CD28, 4-1BB, or dual CD28/4-1BB co-stimulation were evaluated in vitro and in orthotopic G3MB models. Resiquimod was formulated in a brain-penetrant poly (2-oxazoline) nanoparticle (ResiPOx) to activate TLR7/8-expressing myeloid cells. T cell and myeloid states were assessed by flow cytometry, bulk, and single-cell RNA sequencing. RESULTS: CAR designs showed similar tumor control in immunodeficient hosts but diverged in immunocompetent models, where dual-costimulatory CAR T-cells demonstrated superior cytotoxicity and persistence. The optimal CAR induced sustained CAR T-cell cycling and TAM reprogramming while downregulating TLR7/8 in dominant myeloid clusters. ResiPOx enhanced CAR T-cell efficacy by activating myeloid cells and reducing suppressive populations. CONCLUSIONS: Optimized CAR design combined with TLR7/8-mediated myeloid reprogramming enhances T cell activity, supporting TME-guided immunotherapy for G3MB.