Glickstein Bar, Bismuth Mike, Gattegno Roni, Bercovici Tiran, Shaul Oz, Aronovich Ramona, Horn Galit, Levin Anat Globerson, Feng Yi, Ilovitsh Tali
Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, 6997801, Israel.
The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel.
Small. 2025 Mar 10:e2411474. doi: 10.1002/smll.202411474.
Immune checkpoint inhibitors hold promise, yet their efficacy in solid tumors is limited by the complex tumor microenvironment and the lack of immune cell infiltration. This study aims to enhance immunotherapy by combining anti PD-1 checkpoint inhibition therapy with nanodroplet-mediated histotripsy. The proposed method involves systemic injection of nanodroplets, which accumulate within tumors. These nanodroplets are then activated into cavitating gas bubbles using a rotating imaging probe, followed by low-frequency ultrasound application. This process induces tumor fractionation, facilitating the shift of the tumor microenvironment from cold to hot. Tumor ablation results show extensive lesions within the cancerous tissues, demonstrating the effectiveness of the ablation treatment. The combined approach of nanodroplets, ultrasound and anti PD-1 yielded a significant reduction in tumor growth compared to control groups. Immunohistochemistry analysis reveals an increase in F4/80+ macrophages and CD8+ T cells in the treated tumor group, indicating an enhanced immune response. F4/80+ macrophages reached 21.36% ± 3.4%, while CD8+ T-cell recruitment achieved 6.76% ± 4.5%, representing a 6.8- and a 5.5-fold increase compared to the control group, respectively. This approach demonstrates the potential to overcome key barriers in solid tumor treatment by combining precise mechanical disruption with systemic immune activation.
免疫检查点抑制剂具有前景，但其在实体瘤中的疗效受到复杂的肿瘤微环境和免疫细胞浸润缺乏的限制。本研究旨在通过将抗PD-1检查点抑制疗法与纳米液滴介导的组织粉碎术相结合来增强免疫治疗。所提出的方法包括全身注射纳米液滴，纳米液滴在肿瘤内积聚。然后使用旋转成像探头将这些纳米液滴激活成空化气泡，随后施加低频超声。这个过程诱导肿瘤碎裂，促进肿瘤微环境从“冷”向“热”转变。肿瘤消融结果显示癌组织内有广泛的病变，证明了消融治疗的有效性。与对照组相比，纳米液滴、超声和抗PD-1的联合方法使肿瘤生长显著减少。免疫组织化学分析显示，治疗后的肿瘤组中F4/80+巨噬细胞和CD8+ T细胞增加，表明免疫反应增强。F4/80+巨噬细胞达到21.36%±3.4%，而CD8+ T细胞募集达到6.76%±4.5%，分别比对照组增加了6.8倍和5.5倍。这种方法证明了通过将精确的机械破坏与全身免疫激活相结合来克服实体瘤治疗中的关键障碍的潜力。
