Tumor associated fibroblasts (TAFs) are key stromal cells mediating the desmoplastic reaction and being partially responsible for the drug-resistance and immunosuppressive microenvironment formation in solid tumors. Delivery of genotoxic drugs off-targetedly to kill TAFs results in production of Wnt16 which renders the neighboring tumor cells drug resistant as shown in our previous study (PMC4623876). Our current approach looks for means to deactivate, rather than kill, TAFs. Reactive oxygen species (ROS) are the central hub of multiple profibrogenic pathways and indispensable for TAFs activation. Herein, puerarin was identified to effectively downregulate ROS production in the activated myofibroblast. In this study, a novel puerarin nanoemulsion (nanoPue) was developed to improve the solubility and bioavailability of puerarin. NanoPue significantly deactivated the stromal microenvironment (e.g., ~6-fold reduction of TAFs in nanoPue treated mice compared with the PBS control, p < 0.0001) and facilitated chemotherapy effect of nano-paclitaxel in the desmoplastic triple-negative breast cancer (TNBC) model. Moreover, the removal of the physical barrier increased intra-tumoral infiltration of cytotoxic T cell by 2-fold. This activated immune microenvironment allowed nanoPue to synergize PD-L1 blockade therapy in TNBC model.

中文翻译：

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纳米葛根素调节肿瘤微环境并促进小鼠三阴性乳腺癌模型的化疗和免疫治疗。

肿瘤相关成纤维细胞（TAF）是介导促纤维增生反应的关键基质细胞，并部分负责实体瘤中耐药性和免疫抑制微环境的形成。脱靶递送基因毒性药物来杀死 TAF 会导致 Wnt16 的产生，从而使邻近的肿瘤细胞产生耐药性，如我们之前的研究 (PMC4623876) 所示。我们目前的方法是寻找停用而不是杀死 TAF 的方法。活性氧 (ROS) 是多种促纤维化途径的中心枢纽，对于 TAF 激活不可或缺。在此，葛根素被确定可以有效下调活化的肌成纤维细胞中 ROS 的产生。本研究开发了一种新型葛根素纳米乳（nanoPue），以提高葛根素的溶解度和生物利用度。NanoPue 显着使基质微环境失活（例如，与 PBS 对照相比，nanoPue 治疗的小鼠 TAF 减少约 6 倍，p < 0.0001），并促进纳米紫杉醇在促结缔组织增生性三阴性乳腺癌 (TNBC) 模型中的化疗效果。此外，物理屏障的去除使细胞毒性T细胞的肿瘤内浸润增加了2倍。这种激活的免疫微环境使 nanoPue 能够在 TNBC 模型中协同 PD-L1 阻断疗法。