A synergistic approach for modulating the tumor microenvironment to enhance nano-immunotherapy in sarcomas

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 in vivo 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.