High expression of indoleamine 2,3-dioxygenase 1 (IDO1) is a major cause of tumor induced immunosuppression, and appears to be associated with poor prognosis in human colorectal cancer and some others. In this study, we construct a bifunctional liposome by self-assembly of oxaliplatin-prodrug (Oxa(IV)) conjugated phospholipid and alkylated NLG919 (aNLG), an IDO1 inhibitor, together with other commercial lipids. The obtained aNLG/Oxa(IV)-Lip can not only release cytotoxic oxaliplatin inside the reductive cytosol to trigger immunogenic cell death (ICD) of cancer cells, but also efficiently retard the degradation of tryptophan to immunosuppressive kynurenine via the NLG919 mediated inhibition of IDO1. Moreover, in vivo pharmacokinetic studies indicate that such aNLG/Oxa(IV)-Lip has a long blood circulation time, thereby enables highly-efficient passive tumor homing. Upon tumor accumulation, such aNLG/Oxa(IV)-Lip presents superior synergistic antitumor efficacies to both subcutaneous and orthotopic CT26 tumors, ascribing to significantly primed anti-tumor immunity of enhanced intratumoral infiltration of CD8⁺ T cells, scretion of cytotoxic cytokines and downregulation of immunosuppressive regulatory T cells. This work highlights that such bifunctional aNLG/Oxa(IV)-Lip is a potent candidate for future clinical translation owing to its excellent biocompatibility and high therapeutic efficacy.

吲哚胺2,3-二加氧酶1（IDO1）的高表达是肿瘤诱导的免疫抑制的主要原因，并且似乎与人类大肠癌和其他一些人的预后不良有关。在这项研究中，我们通过奥沙利铂前药（Oxa（IV））共轭磷脂和烷基化NLG919（aNLG）（一种IDO1抑制剂）与其他商业脂质的自组装构建了一种双功能脂质体。获得的aNLG / Oxa（IV）-Lip不仅可以释放还原性细胞溶胶内的细胞毒性奥沙利铂以触发癌细胞的免疫原性细胞死亡（ICD），还可以通过NLG919介导的IDO1抑制作用有效地抑制色氨酸降解为免疫抑制型犬尿氨酸。 。此外，体内药代动力学研究表明，此类aNLG / Oxa（IV）-Lip具有较长的血液循环时间，从而实现高效的被动肿瘤归巢。在肿瘤积累后，此类aNLG / Oxa（IV）-Lip对皮下和原位CT26肿瘤均表现出优异的协同抗肿瘤功效，这归因于CD8增强的肿瘤内浸润的显着抗肿瘤免疫力⁺ T细胞，细胞毒性细胞因子的分泌和免疫抑制调节性T细胞的下调。这项工作突显了这种双功能aNLG / Oxa（IV）-Lip由于其出色的生物相容性和高治疗功效而成为未来临床翻译的有效候选者。