Banstola Asmita, Pandit Mahesh, Duwa Ramesh, Chang Jae-Hoon, Jeong Jee-Heon, Yook Simmyung
College of Pharmacy Keimyung University Daegu South Korea.
Department of Dermatology, Harvard Medical School Wellman Center for Photomedicine, Massachusetts General Hospital Boston Massachusetts USA.
Bioeng Transl Med. 2022 Aug 3;8(5):e10379. doi: 10.1002/btm2.10379. eCollection 2023 Sep.
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.
开发一种优化的治疗方式以改善乳腺癌患者的治疗效果仍然很困难。向T细胞呈递抗原不足是癌症免疫治疗中的一个主要挑战。在本研究中，报道了一种用于乳腺癌的协同免疫治疗策略，该策略通过活性氧（ROS）响应性双靶向智能纳米系统（抗PD-L1-TKNP）在肿瘤微环境中同时释放阿霉素（DOX）、R848和巨噬细胞炎性蛋白-3α（MIP-3α），从而实现免疫细胞浸润、免疫原性细胞死亡（ICD）和树突状细胞（DC）成熟。局部注射后，抗PD-L1-DOX-R848-MIP-3α/硫酮缩醛纳米颗粒（TKNP）由于DOX诱导的ICD、R848介导的免疫刺激特性以及MIP-3α在肿瘤微环境中诱导的免疫细胞募集的联合作用，将肿瘤细胞转化为疫苗。瘤内注射抗PD-L1-DOX-R848-MIP-3α/TKNP可导致乳腺癌显著消退。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）和高迁移率族蛋白B1（HMGB1）最大程度暴露，并显著增强肿瘤内CD4和CD8 T细胞的浸润。因此，使用双靶向ROS响应性TKNP的联合策略突出了纳米颗粒在调节肿瘤微环境中的重要应用，可能是有效管理乳腺癌的一种临床治疗策略。
