Shanghai Skin Disease Hospital, The Institute for Biomedical Engineering & Nano Science, School of Medicine, Tongji University, Shanghai, 200092, China.
Institute of Acoustics, School of Physics Science and Engineering, Tongji University, Shanghai, 200092, China.
Biomaterials. 2022 May;284:121516. doi: 10.1016/j.biomaterials.2022.121516. Epub 2022 Apr 9.
Tumor hyaluronan (HA) accumulation is closely associated with the formation of a hypoxic microenvironment that is highly immunosuppressive and severely hinders the efficacy of antitumor therapeutics. To address this problem, we develop an effective HA attenuation strategy that uses an integrated nanosystem based on mesoporous polydopamine (mPDA) with excellent photothermal conversion efficiency to boost hyaluronidase (HAase) activity remotely. Upon light irradiation, the thermal effect generated by mPDA not only directly kills tumor cells that produces an in situ vaccine effect, but also significantly boosts HAase activity (∼5 folds), leading to marked HA break down. Photoheat and HA degradation synergistically reduce tumor HIF-1α expression and reverse immunosuppressive responses. Using the synergistic treatment in a breast cancer model, we find decreased infiltration of immunosuppressive cells, including myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells, increased immune-activated cells, such as mature dendritic cells and CD8 T cells, and reduced immune checkpoint PD-L1 expression. The resulting relief from tumor microenvironment immunosuppression significantly contributes to an enhanced antitumor effect. This study provides an effective strategy to improve the hypoxic tumor microenvironment and simultaneously promote immune-mediated tumor regression.
肿瘤透明质酸（HA）的积累与缺氧微环境的形成密切相关，这种微环境高度免疫抑制，严重阻碍了抗肿瘤治疗的效果。为了解决这个问题，我们开发了一种有效的 HA 衰减策略，该策略使用基于介孔聚多巴胺（mPDA）的集成纳米系统，具有优异的光热转换效率，可远程增强透明质酸酶（HAase）的活性。在光照射下，mPDA 产生的热效应不仅可以直接杀死产生原位疫苗效应的肿瘤细胞，还可以显著提高 HAase 的活性（约 5 倍），导致 HA 的明显降解。光热和 HA 降解协同降低肿瘤 HIF-1α 的表达并逆转免疫抑制反应。在乳腺癌模型中，我们发现使用协同治疗后，抑制性细胞（包括髓源性抑制细胞、M2 巨噬细胞和调节性 T 细胞）的浸润减少，免疫激活细胞（如成熟树突状细胞和 CD8 T 细胞）增加，免疫检查点 PD-L1 的表达减少。肿瘤微环境免疫抑制的缓解显著有助于增强抗肿瘤作用。这项研究提供了一种有效的策略来改善缺氧肿瘤微环境，同时促进免疫介导的肿瘤消退。
