School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
College of Life and Health Sciences, Anhui Science and Technology University, Fengyang 233100, China.
Int J Pharm. 2024 Dec 25;667(Pt A):124860. doi: 10.1016/j.ijpharm.2024.124860. Epub 2024 Oct 24.
Modulating the immunosuppressive tumor microenvironment (TME) while enhancing antitumor immune responses is a promising strategy. In this study, we designed an acid-sensitive nanosystem (MCCaNPs) to demonstrate effective immunotherapy against cancer through the systemic delivery of immune-stimulating chemotherapy combinations. A pH-responsive nanoplatform containing CaCO was prepared by the double emulsion method, and mitoxantrone (MIT) and celastrol (CEL) were simultaneously encapsulated as immunogenic cell death (ICD) inducers. Due to the acid responsiveness of CaCO, the nanoparticles rapidly consume H to relieve the acidic tumor microenvironment and explosively release CEL and MIT, showing inherent immunomodulatory activity in collaborative tumor chemoimmunotherapy. MIT and CEL synergistically trigger stronger ICD by inducing tumor cells to release calreticulin (CRT), high mobility group box 1 protein (HMGB1). Following the intravenous administration of MCCaNPs, the local tumor microenvironment(TME) was reprogrammed in mice-bearing tumors. This reprogramming was characterized by a significant increase in the density of tumor-infiltrating cytotoxic T lymphocytes(CTLs), ultimately prolonging survival. Therefore, this research proposes a promising approach to trigger immunogenic cell death collaboratively, aiming to boost the tumor CTLs infiltration for anticancer immunotherapy.
调节免疫抑制性肿瘤微环境（TME）同时增强抗肿瘤免疫反应是一种很有前途的策略。在本研究中，我们设计了一种酸敏纳米系统（MCCaNPs），通过系统递送免疫刺激化疗联合来展示针对癌症的有效免疫治疗。采用复乳法制备了含有 CaCO 的 pH 响应性纳米平台，并同时包封米托蒽醌（MIT）和雷公藤红素（CEL）作为免疫原性细胞死亡（ICD）诱导剂。由于 CaCO 的酸响应性，纳米颗粒迅速消耗 H+以缓解酸性肿瘤微环境，并暴发性释放 CEL 和 MIT，在协同肿瘤化疗免疫治疗中表现出固有免疫调节活性。MIT 和 CEL 通过诱导肿瘤细胞释放钙网织蛋白（CRT）和高迁移率族蛋白 B1（HMGB1）协同触发更强的 ICD。在荷瘤小鼠中静脉注射 MCCaNPs 后，局部肿瘤微环境（TME）被重新编程。这种重编程的特征是肿瘤浸润性细胞毒性 T 淋巴细胞（CTLs）的密度显著增加，最终延长了生存期。因此，本研究提出了一种有前途的协同触发免疫原性细胞死亡的方法，旨在促进肿瘤 CTLs 浸润以进行抗癌免疫治疗。
