Immunogenic chemotherapy (IC) is a type of chemotherapy where certain chemodrugs induce immunogenic cancer cell death (ICD), which in turn arouses T cell antitumor immunity. However, IC concurrently upregulates a key immune suppressor, indoleamine-2,3-dioxygenase (IDO), in both cancer cells and immune cells. IDO-mediated immunosuppression significantly offsets IC's therapeutic benefits in cancer patients, suggesting a necessity of combination with IDO inhibitors. Here, we report an enzyme-, pH-, and redox-triple-sensitive nanosystem using mesoporous silica nanoparticles (MSNs) as a core encapsulating doxorubicin (DOX, an immunogenic chemodrug); the core is coated with a shell (β-CD-PEI/Ge1MT) for co-delivering 1-methyl-D-tryptophan (1 MT, an IDO inhibitor). By using these responsivenesses sequentially triggering the release of 1 MT into tumor extracellular compartment and DOX into intracellular endo/lysosomal compartment, this nanosystem (DOX@GMTMSNs) precisely delivers the drugs to their target cells residing in different compartments. Released 1 MT uptake by IDO-expressing dendritic cells (DCs) and cancer cells suppresses IDO activity, reducing immunosuppressive Tregs' presence; DOX unloaded within cancer cells induces ICD, promoting effector T-cell infiltration. In two preclinical cancer models, DOX@GMTMSNs potentiate both tumor local and systemic antitumor immunity, suppressing primary tumor growth by 78% with an 83% reduction in metastatic foci, as well as extending animal survival, thus strongly demonstrating DOX@ GMTMSNs' clinical translational potential.

免疫原化学疗法（IC）是一种化学疗法，其中某些化学药物会诱导免疫原性癌细胞死亡（ICD），从而引起T细胞抗肿瘤免疫力。但是，IC同时在癌细胞和免疫细胞中上调了关键的免疫抑制剂吲哚胺-2,3-二加氧酶（IDO）。IDO介导的免疫抑制作用显着抵消了IC对癌症患者的治疗益处，表明必须与IDO抑制剂联合使用。在这里，我们报道了一种酶，pH和三重氧化还原敏感的纳米系统，该系统使用中孔二氧化硅纳米粒子（MSNs）作为核心包裹阿霉素（DOX，一种免疫原性化学药物）。核被壳包裹（β-CD-PEI / Ge1MT）共同递送1-甲基-D-色氨酸（1 MT，IDO抑制剂）。通过利用这些反应性，依次触发1 MT释放到肿瘤细胞外区室和DOX释放到细胞内内/溶酶体区室，该纳米系统（DOX @ GMTMSN）精确地将药物递送至位于不同区室的靶细胞。表达IDO的树突状细胞（DC）和癌细胞释放的1 MT摄取抑制了IDO活性，减少了免疫抑制性Treg的存在。癌细胞中未装载的DOX诱导ICD，促进效应T细胞浸润。 在两个临床前癌症模型中，DOX @ GMTMSNs增强了肿瘤的局部和全身抗肿瘤免疫力，将原发性肿瘤生长抑制了78％，转移灶减少了83％，并延长了动物的存活率，从而有力地证明了DOX @ GMTMSNs的临床意义潜在。