The development of an optimal treatment modality to improve the therapeutic outcome of breast cancer patients is still difficult. Poor antigen presentation to T cells is a major challenge in cancer immunotherapy. In this study, a synergistic immunotherapy strategy for breast cancer incorporating immune cell infiltration, immunogenic cell death (ICD), and dendritic cell (DC) maturation through a reactive oxygen species (ROS)-responsive dual-targeted smart nanosystem (anti-PD-L1-TKNP) for the simultaneous release of DOX, R848, and MIP-3α in the tumor microenvironment is reported. Following local injection, anti-PD-L1-DOX-R848-MIP-3α/thioketal nanoparticle (TKNP) converts tumor cells to a vaccine owing to the combinatorial effect of DOX-induced ICD, R848-mediated immunostimulatory properties, and MIP-3α-induced immune cell recruitment in the tumor microenvironment. Intratumoral injection of anti-PD-L1-DOX-R848-MIP-3α/TKNP caused significant regression of breast cancer. Mechanistic studies reveal that anti-PD-L1-DOX-R848-MIP-3α/TKNP specifically targets tumor tissue, resulting in maximum exposure of calreticulin (CRT) and HMGB1 in tumors, and significantly enhances intratumoral infiltration of CD4⁺ and CD8⁺ T cells in tumors. Therefore, a combined strategy using dual-targeted ROS-responsive TKNP highlights the significant application of nanoparticles in modulating the tumor microenvironment and could be a clinical treatment strategy for effective breast cancer management.

中文翻译：

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活性氧响应双靶向纳米系统促进乳腺癌免疫原性细胞死亡

开发最佳治疗方式来改善乳腺癌患者的治疗结果仍然很困难。T 细胞抗原呈递不良是癌症免疫治疗的主要挑战。在这项研究中，乳腺癌的协同免疫治疗策略通过活性氧（ROS）响应的双靶向智能纳米系统（抗PD-据报道，L1-TKNP) 可在肿瘤微环境中同时释放 DOX、R848 和 MIP-3α。局部注射后，由于 DOX 诱导的 ICD、R848 介导的免疫刺激特性和 MIP-3α 的组合作用，抗 PD-L1-DOX-R848-MIP-3α/thioketal 纳米颗粒 (TKNP) 将肿瘤细胞转化为疫苗-在肿瘤微环境中诱导免疫细胞募集。瘤内注射抗PD-L1-DOX-R848-MIP-3α/TKNP引起乳腺癌显着消退。机制研究表明，抗PD-L1-DOX-R848-MIP-3α/TKNP特异性靶向肿瘤组织，导致肿瘤中钙网蛋白（CRT）和HMGB1的最大暴露，并显着增强CD4 + 和CD8 + T^的瘤^内浸润肿瘤中的细胞。因此，使用双靶点 ROS 响应 TKNP 的组合策略凸显了纳米颗粒在调节肿瘤微环境中的重要应用，并可能成为有效乳腺癌管理的临床治疗策略。