Abstract：
Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.
摘要：
吲哚胺2,3-双加氧酶（IDO），在肝细胞癌（HCC）中高表达，在创造免疫抑制肿瘤微环境中起着关键作用。抑制IDO活性已成为一种有前途的免疫治疗策略；然而，IDO抑制剂向肿瘤部位的递送受到限制，限制其治疗效果。在这项研究中,我们开发了一种用于靶向递送IDO抑制剂NLG919的磁性涡旋纳米递送系统,该系统与磁性热疗相结合,以逆转肝癌的免疫抑制微环境并抑制肿瘤生长.该系统包括加载有NLG919(NLG919/PI-FVIOs)的热响应性聚乙烯亚胺涂覆的亚铁磁性涡流畴氧化铁纳米环(PI-FVIOs)。在热效应下，NLG919可以精确地从输送系统中释放，对抗IDO介导的免疫抑制，并与NLG919/PI-FVIOs介导的磁热力学（MTD）治疗诱导的免疫原性细胞死亡（ICD）协同作用，导致有效的HCC抑制。体内研究表明，这种联合疗法通过增强细胞毒性T淋巴细胞的积累和抑制肿瘤内的调节性T细胞来显著抑制肿瘤生长和转移。总的来说,我们的研究结果表明，NLG919/PI-FVIOs可以通过破坏IDO途径和激活ICD来诱导有效的抗肿瘤免疫应答，为肝癌治疗提供了一个有希望的治疗途径。
