Abstract：
Integrating immunotherapy with nanomaterials-based chemotherapy presents a promising avenue for amplifying antitumor outcomes. Nevertheless, the suppressive tumor immune microenvironment (TIME) and the upregulation of cyclooxygenase-2 (COX-2) induced by chemotherapy can hinder the efficacy of the chemoimmunotherapy. This study presents a TIME-reshaping strategy by developing a steric-hindrance effect tuned zinc-based metal-organic framework (MOF), designated as CZFNPs. This nanoreactor is engineered by in situ loading of the COX-2 inhibitor, C-phycocyanin (CPC), into the framework building blocks, while simultaneously weakening the stability of the MOF. Consequently, CZFNPs achieve rapid pH-responsive release of zinc ions (Zn2+) and CPC upon specific transport to tumor cells overexpressing folate receptors. Accordingly, Zn2+ can induce reactive oxygen species (ROS)-mediated cytotoxicity therapy while synchronize with mitochondrial DNA (mtDNA) release, which stimulates mtDNA/cGAS-STING pathway-mediated innate immunity. The CPC suppresses the chemotherapy-induced overexpression of COX-2, thus cooperatively reprogramming the suppressive TIME and boosting the antitumor immune response. In xenograft tumor models, the CZFNPs system effectively modulates STING and COX-2 expression, converting \"cold\" tumors into \"hot\" tumors, thereby resulting in ≈ 4-fold tumor regression relative to ZIF-8 treatment alone. This approach offers a potent strategy for enhancing the efficacy of combined nanomaterial-based chemotherapy and immunotherapy.
摘要：
将免疫疗法与基于纳米材料的化学疗法整合为放大抗肿瘤结果提供了有希望的途径。然而，化疗引起的抑制性肿瘤免疫微环境（TIME）和环氧合酶-2（COX-2）上调可能会阻碍化学免疫治疗的疗效。这项研究通过开发空间位阻效应调节的锌基金属有机框架（MOF）提出了一种时间重塑策略，指定为CZFNP。这种纳米反应器是通过原位加载COX-2抑制剂而设计的，C-藻蓝蛋白(CPC),进入框架构建块，同时削弱了MOF的稳定性。因此,CZFNP在特异性转运至过度表达叶酸受体的肿瘤细胞时实现锌离子(Zn2+)和CPC的快速pH响应性释放。因此，Zn2+可以诱导活性氧（ROS）介导的细胞毒性治疗，同时与线粒体DNA（mtDNA）释放同步，刺激mtDNA/cGAS-STING通路介导的先天免疫。CPC抑制化疗诱导的COX-2过表达，从而共同重新编程抑制性TIME并增强抗肿瘤免疫反应。在异种移植肿瘤模型中，CZFNPs系统有效调节STING和COX-2表达，将“冷”肿瘤转化为“热”肿瘤，从而导致相对于单独的ZIF-8治疗约4倍的肿瘤消退。这种方法为增强基于纳米材料的联合化疗和免疫疗法的功效提供了有效的策略。
