The lack of properly perfused blood vessels within tumors can significantly hinder the distribution of drugs, leading to reduced treatment effectiveness and having a negative impact on the quality of life of patients with cancer. This problem is particularly pronounced in desmoplastic cancers, where interactions between cancer cells, stromal cells, and the fibrotic matrix lead to tumor stiffness and the compression of most blood vessels within the tumor. To address this issue, two mechanotherapy approaches–mechanotherapeutics and ultrasound sonopermeation–have been employed separately to treat vascular abnormalities in tumors and have reached clinical trials. Here, we performed studies in sarcomas, to explore the conditions under which these two mechanotherapy strategies could be optimally combined to enhance perfusion and the efficacy of nano-immunotherapy. Our findings demonstrate that combination of the anti-histamine drug ketotifen, as a mechanotherapeutic, and sonopermeation effectively alleviates mechanical forces by decreasing 50 % collagen and hyaluronan levels and thus, reshaping the tumor microenvironment. Furthermore, the combined therapy normalizes the tumor vasculature by increasing two-fold the pericytes coverage. This combination not only improves six times tumor perfusion but also enhances drug delivery. As a result, blood vessel functionality is enhanced, leading to increased infiltration by 40 % of immune cells (CD4 and CD8 T-cells) and improving the antitumor efficacy of Doxil nanomedicine and anti-PD-1 immunotherapy. In conclusion, our research underscores the unique and synergistic potential of combining mechanotherapeutics and sonopermeation. Both approaches are undergoing clinical trials to enhance cancer therapy and have the potential to significantly improve nano-immunotherapy in sarcomas.

中文翻译：

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调节肿瘤微环境以增强肉瘤纳米免疫治疗的协同方法

肿瘤内缺乏适当灌注的血管会严重阻碍药物的分布，导致治疗效果降低并对癌症患者的生活质量产生负面影响。这个问题在促结缔组织增生性癌症中尤其明显，其中癌细胞、基质细胞和纤维化基质之间的相互作用导致肿瘤僵硬和肿瘤内大多数血管受压。为了解决这个问题，两种机械治疗方法——机械治疗和超声渗透——已分别用于治疗肿瘤中的血管异常，并已进入临床试验。在这里，我们对肉瘤进行了研究，以探索在什么条件下可以将这两种机械疗法策略最佳地结合起来，以增强灌注和纳米免疫疗法的功效。我们的研究结果表明，抗组胺药物酮替芬作为机械治疗剂与超声波渗透相结合，可降低 50% 的胶原蛋白和透明质酸水平，从而有效减轻机械力，从而重塑肿瘤微环境。此外，联合疗法通过将周细胞覆盖率增加两倍来使肿瘤脉管系统正常化。这种组合不仅将肿瘤灌注提高了六倍，而且还增强了药物输送。结果，血管功能得到增强，导致免疫细胞（CD4 和 CD8 T 细胞）的浸润增加 40%，并提高 Doxil 纳米药物和抗 PD-1 免疫疗法的抗肿瘤功效。总之，我们的研究强调了机械治疗和声波渗透相结合的独特和协同潜力。这两种方法正在进行临床试验，以增强癌症治疗，并有可能显着改善肉瘤的纳米免疫治疗。