The hypoxic and immunosuppressive tumor microenvironment (TME) remains a major obstacle to impede cancer immunotherapy. Here, we found that sononeoperfusion—a new effect of tumor perfusion enhancement induced by low mechanical index ultrasound stimulated microbubble cavitation (USMC)—ameliorated tumor tissue oxygenation and induced tumor vascular normalization (TVN). This TVN might be associated with the down-regulation of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) within tumors. Moreover, the sononeoperfusion effect reduced the accumulation of immunosuppressive cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2-like tumor-associated macrophages (M2-TAMs), and decreased the production of immune inhibitory factors like transforming growth factor-β1 (TGF-β1), interleukin 10 (IL-10), chemoattractant chemokines CC-chemokine ligand 22 (CCL22), CCL28, adenosine and lactate within tumors. Notably, flow cytometry analysis revealed that sononeoperfusion not only increased the percentage of tumor infiltrating-CD8+ T cells, but also promoted the generation of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) by these cells. Furthermore, the improved immune TME by sononeoperfusion effect sensitized anti-PD-L1 treatment both in MC38 colon cancer and Lewis lung carcinoma mice, resulting in tumor regression and prolonged survival. Mechanically, the enhanced efficacy of combination therapy was mainly based on promoting the infiltration and function of CD8+ T cells within tumors. Together, sononeoperfusion could ameliorate hypoxia and immunosuppression in the TME, thereby potentiating anti-PD-L1 therapy for solid tumors. This novel method of USMC generating sononeoperfusion effect may provide a new therapeutic modality for facilitating cancer immunotherapy.

中文翻译：

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通过 Sononeoperfusion 缓解肿瘤缺氧和免疫抑制：增强抗 PD-L1 阻断实体瘤的新盟友


缺氧和免疫抑制性肿瘤微环境 （TME） 仍然是阻碍癌症免疫治疗的主要障碍。在这里，我们发现 sononeoperfusion——由低机械指数超声刺激微泡空化 （USMC） 诱导的肿瘤灌注增强的新作用——改善了肿瘤组织氧合并诱导了肿瘤血管正常化 （TVN）。这种 TVN 可能与肿瘤内缺氧诱导因子 1-α （HIF-1α） 和血管内皮生长因子 （VEGF） 的下调有关。此外，声酮灌注作用减少了免疫抑制细胞的积累，如调节性 T 细胞 （Tregs）、髓源性抑制细胞 （MDSC） 和 M2 样肿瘤相关巨噬细胞 （M2-TAM），并减少了免疫抑制因子如转化生长因子-β 1 （TGF-β1） 、白细胞介素 10 （IL-10）、趋化因子 CC-趋化因子配体 22 （CCL22）、CCL28、腺苷和乳酸肿瘤内的产生。值得注意的是，流式细胞术分析显示，sononeoperfusion 不仅增加了肿瘤浸润 CD8+ T 细胞的百分比，还促进了这些细胞产生干扰素-γ （IFN-γ） 和肿瘤坏死因子-α （TNF-α）。此外，sononeoperfusion 效应改善的免疫 TME 使 MC38 结肠癌和 Lewis 肺癌小鼠的抗 PD-L1 治疗敏感，导致肿瘤消退和生存期延长。从机械上讲，联合治疗的疗效增强主要基于促进肿瘤内 CD8+ T 细胞的浸润和功能。总之，sononeoperfusion 可以改善 TME 中的缺氧和免疫抑制，从而增强实体瘤的抗 PD-L1 治疗。 这种 USMC 产生声音灌注效应的新方法可能为促进癌症免疫治疗提供一种新的治疗方式。