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Background Group 3 medulloblastoma (G3MB) is the most aggressive medulloblastoma subgroup. Although CAR T-cell therapy is promising, it has shown limited efficacy in G3MB due to poor T-cell persistence, largely driven by the immunosuppressive tumor microenvironment (TME) and an intact blood-brain barrier (BBB). M2-like tumor-associated macrophages (TAMs) are major contributors to this immunosuppression, whereas inflammatory TAMs can support CAR T-cell function. We identified Resiquimod, a Toll-like receptor (TLR) 7/8 agonist, as a potent immunomodulator capable of reprogramming TAMs toward a pro-inflammatory phenotype. In parallel, low-intensity focused ultrasound (LIFU) provides a noninvasive method to transiently disrupt the BBB, potentially enhancing both immunomodulatory effects and CAR T-cell infiltration. The objective of this study is to improve the efficacy of B7-H3-directed CAR T-cell therapy in G3MB by optimizing CAR design, reprogramming the TME using POx-encapsulated Resiquimod (POx-R), and enhancing tumor accessibility with LIFU.Methods We engineered B7-H3 CARs with CD28, 4-1BB, or dual costimulatory domains and tested their efficacy in vitro and in vivo. POx-R was administered systemically to enable brain penetration and TAM repolarization. LIFU was applied with microbubbles to transiently open the BBB and facilitate delivery of CAR T-cells. Immune profiling included flow cytometry and RNA sequencing.Results In vitro, CAR T-cells with dual CD28 and 4-1BB costimulatory domains demonstrated superior cytotoxicity and persistence. In vivo, systemically administered POx-R effectively crossed the BBB and induced pro-inflammatory TAM repolarization, as evidenced by upregulation of M1 markers and inflammatory cytokines detected by bulk RNA sequencing and flow cytometry. Preliminary data also indicate enhanced CAR T-cell infiltration and TME remodeling when combined with LIFU-mediated BBB disruption. Ongoing studies aim to elucidate the underlying mechanisms and optimize treatment scheduling to maximize therapeutic synergy.Conclusions This multimodal strategy integrating CAR engineering, myeloid reprogramming, and BBB modulation offers a promising path to overcome the key barriers limiting CAR T-cell therapy in G3MB.