Epacadostat (EPA) 是最先进的 IDO1 抑制剂，与 PD-1 检查点抑制剂联合使用，在最近一项治疗转移性黑色素瘤的 III 期临床试验中失败。在这里，我们报道了一种 EPA 纳米囊泡治疗平台（Epacasome），该平台基于通过对水解酶裂解高度敏感的肟-酯键将 EPA 化学连接到鞘磷脂上。通过网格蛋白介导的内吞作用，与游离 EPA 相比，Epacasome 显示出更高的细胞摄取并增强 IDO1 抑制和 T 细胞增殖。 Epacasome 显示出改善的药代动力学和肿瘤积累，具有有效的肿瘤内药物释放和深度肿瘤渗透。此外，它的抗癌功效优于游离 EPA，在雌性小鼠 B16-F10 黑色素瘤模型中，通过增强细胞毒性 T 淋巴细胞 (CTL) 并减少调节性 T 细胞和骨髓源性抑制细胞反应来增强 PD-1 阻断作用。通过共封装免疫原性达卡巴嗪，Epacasome 通过上调 NKG2D 介导的 CTL 和自然杀伤细胞反应，进一步增强抗肿瘤作用和免疫反应，特别是与晚期转移性 B16-F10-Luc2 中的 PD-1 抑制剂联合使用时雌性小鼠模型。此外，在雌性小鼠的临床相关术后黑色素瘤模型中，这种组合可以防止肿瘤复发并延长小鼠的生存期。 Epacasome 表现出与 PD-1 阻断剂协同作用以改善黑色素瘤免疫治疗反应的潜力。© 2023。作者。

Epacadostat (EPA), the most advanced IDO1 inhibitor, in combination with PD-1 checkpoint inhibitor, has failed in a recent Phase III clinical trial for treating metastatic melanoma. Here we report an EPA nanovesicle therapeutic platform (Epacasome) based on chemically attaching EPA to sphingomyelin via an oxime-ester bond highly responsive to hydrolase cleavage. Via clathrin-mediated endocytosis, Epacasome displays higher cellular uptake and enhances IDO1 inhibition and T cell proliferation compared to free EPA. Epacasome shows improved pharmacokinetics and tumour accumulation with efficient intratumoural drug release and deep tumour penetration. Additionally, it outperforms free EPA for anticancer efficacy, potentiating PD-1 blockade with boosted cytotoxic T lymphocytes (CTLs) and reduced regulatory T cells and myeloid-derived suppressor cells responses in a B16-F10 melanoma model in female mice. By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy.© 2023. The Author(s).