Zhao Zhenhao, Li Chufeng, Zhang Yiwen, Li Chao, Chu Yongchao, Li Xuwen, Liu Peixin, Chen Hongyi, Wang Yu, Su Boyu, Chen Qinjun, Sun Tao, Jiang Chen
Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai, 201203, China.
Bioact Mater. 2023 Apr 27;27:474-487. doi: 10.1016/j.bioactmat.2023.04.021. eCollection 2023 Sep.
A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients. Here, we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nanomaterials (SIL@T). SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells, releasing silybin and oxaliplatin responsively in the cells. SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals. Mechanistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells, activate immune responses and increase infiltration of CD8 T cells. Meanwhile, the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed. This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases.
长期以来有效治疗方法的匮乏导致三阴性乳腺癌脑转移的预后较差。免疫疗法在肿瘤治疗方面取得了进展,但受肿瘤的非免疫原性和强大的免疫抑制环境限制,三阴性乳腺癌脑转移患者尚未从免疫疗法中获益。增强免疫激活和逆转免疫抑制微环境的双重免疫调节策略为患者提供了新的治疗选择。在此,我们提出一种类似鸡尾酒的微环境调节-化疗-免疫协同增敏治疗策略,并构建还原敏感的免疫微环境调节纳米材料(SIL@T)。用靶向肽修饰的SIL@T穿透血脑屏障,随后被转移性乳腺癌细胞内化,在细胞内响应性释放水飞蓟宾和奥沙利铂。SIL@T优先在转移部位蓄积,并能显著延长模型动物的生存期。机制研究表明,SIL@T能有效诱导转移细胞的免疫原性细胞死亡,激活免疫反应并增加CD8 T细胞浸润。同时,转移灶中STAT3的激活减弱,免疫抑制微环境得到逆转。本研究表明,具有双重免疫调节功能的SIL@T为乳腺癌脑转移提供了一种有前景的免疫协同治疗策略。