Remotely boosting hyaluronidase activity to normalize the hypoxic immunosuppressive tumor microenvironment for photothermal immunotherapy
Remotely boosting hyaluronidase activity to normalize the hypoxic immunosuppressive tumor microenvironment for photothermal immunotherapy
复制标题
远程增强透明质酸酶活性，使光热免疫治疗的缺氧免疫抑制肿瘤微环境正常化
DOI：
10.1016/j.biomaterials.2022.121516
复制
发表时间：
2022-04-15
期刊：
影响因子：
14
通讯作者：
Li, Yongyong
中科院分区：
文献类型：
--
作者：
Liu, Yiqiong;Xu, Dailin;Li, Yongyong
肿瘤透明质酸（HA）的积累与低氧微环境的形成密切相关，低氧微环境具有高度的免疫抑制作用，严重阻碍了抗肿瘤治疗的疗效。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，以远程提高透明质酸酶（HAase）的活性。在光照射下，mPDA产生的热效应不仅能直接杀死肿瘤细胞，产生原位疫苗效应，还能显著提高HAase活性（约5倍），导致HA明显分解。光热和透明质酸降解协同降低肿瘤HIF-1 α表达并逆转免疫抑制反应。在乳腺癌模型中使用协同治疗，我们发现免疫抑制细胞（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）的浸润增加，免疫检查点PD-L1的表达降低。由此产生的肿瘤微环境免疫抑制的缓解显著有助于增强抗肿瘤作用。本研究为改善低氧肿瘤微环境，同时促进免疫介导的肿瘤消退提供了有效的策略。
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-1 alpha 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.