Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX). Intravenous injection of the encapsulated two-drug combination dramatically improved the pharmacokinetics and tumor drug concentrations of DOX and IND in an orthotopic 4T1 tumor model in syngeneic mice. Delivery of a threshold ICD stimulus resulted in the uptake of dying BC cells by dendritic cells, tumor antigen presentation and the activation/recruitment of naı̈ve T-cells. The subsequent activation of perforin- and IFN-γ releasing cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites. Immune phenotyping of the tumor tissues confirmed the recruitment of CD8+ cytotoxic T lymphocytes (CTLs), disappearance of Tregs, and an increase in CD8+/FOXP3+ T-cell ratios. Not only does the DOX/IND-Liposome provide a synergistic antitumor response that is superior to a DOX-only liposome, but it also demonstrated that the carrier could be effectively combined with PD-1 blocking antibodies to eradicate lung metastases. All considered, an innovative nano-enabled approach has been established to allow deliberate use of ICD to switch an immune deplete to an immune replete BC microenvironment, allowing further boosting of the response by coadministered IDO inhibitors or immune checkpoint blocking antibodies.

中文翻译：

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通过脂质体递送免疫原性细胞死亡刺激物以及对 IDO-1 通路的干扰进行乳腺癌化学免疫疗法。

免疫疗法提供了降低转移性乳腺癌 (BC) 高死亡率的最佳方法。我们展示了一种化学免疫治疗方法，该方法利用脂质体载体同时触发免疫原性细胞死亡 (ICD)，并干扰 BC 肿瘤部位吲哚胺 2,3-双加氧酶 (IDO-1) 的区域过度表达免疫抑制作用。脂质体是通过磷脂结合的前药吲哚昔莫德 (IND) 的自组装构建的，该药物抑制 IDO-1 通路，然后远程加载诱导 ICD 的化疗药物阿霉素 (DOX)。在同基因小鼠的原位 4T1 肿瘤模型中，静脉注射封装的两种药物组合显着改善了 DOX 和 IND 的药代动力学和肿瘤药物浓度。阈值 ICD 刺激的传递导致树突状细胞吸收垂死的 BC 细胞、肿瘤抗原呈递和幼稚 T 细胞的激活/募集。随后激活穿孔素和 IFN-γ 释放细胞毒性 T 细胞，在原发和转移肿瘤部位诱导强烈的肿瘤细胞杀伤。肿瘤组织的免疫表型证实了 CD8+ 细胞毒性 T 淋巴细胞 (CTL) 的募集、Treg 的消失以及 CD8+/FOXP3+ T 细胞比率的增加。DOX/IND-Liposome 不仅提供了优于 DOX-only 脂质体的协同抗肿瘤反应，而且还证明了载体可以有效地与 PD-1 阻断抗体结合以根除肺转移。都考虑过，