Nanomedicine-based phototherapy in combination with immune checkpoint blockade therapy has been reported as a promising strategy for improved cancer immunotherapy. However, tumor penetration of nanomedicine into solid tumor is still an unresolved obstacle to an effective drug delivery, leading to limitations in their applications. Here, we developed a tumor microenvironment-responsive prodrug nanoplatform for efficient penetration and photo-immunotherapy of cancer. The prodrug nanoplatform is performed by integrating PEGylated indoleamine-2,3-dioxygenase (IDO) inhibitor (Epacadostat) and photosensitizer (Indocyanine green, ICG) into a core-shell nanostructure via intermolecular interactions, which can transform into small dual-drug complexes (<40 nm) at tumor microenvironment. The resulting small dual-drug complexes could undergo caveolae-mediated endocytosis, enhance cellular uptake, directly kill tumor cells, in situ trigger antitumor immune response and modulate IDO-mediated immunosuppression. More significantly, the prodrug nanoplatform in combination with PD-L1 checkpoint blockade synergistically promoted the antitumor immunity and efficiently inhibited the growth of both primary and abscopal tumors. The present study provides a novel delivery strategy for nanoenabled phototherapy and IDO inhibition to combine PD-L1 checkpoint blockade for achieving more effective therapy of solid tumors.

据报道，基于纳米医学的光疗与免疫检查点阻断疗法相结合是改善癌症免疫治疗的一种有前途的策略。然而，纳米药物向实体瘤的肿瘤渗透仍然是有效药物递送的未解决的障碍，导致其应用受到限制。在这里，我们开发了一种肿瘤微环境响应性前药纳米平台，用于癌症的有效渗透和光免疫治疗。该前药纳米平台是通过分子间相互作用将聚乙二醇化吲哚胺-2,3-双加氧酶（IDO）抑制剂（Epacadostat）和光敏剂（吲哚青绿，ICG）整合到核壳纳米结构中，可以转化为小型双药复合物（ <40 id=6>原位触发抗肿瘤免疫反应并调节IDO介导的免疫抑制。更重要的是，前药纳米平台与PD-L1检查点阻断相结合可协同促进抗肿瘤免疫并有效抑制原发性和远隔肿瘤的生长。本研究为纳米光疗和 IDO 抑制提供了一种新颖的递送策略，将 PD-L1 检查点阻断结合起来，以实现更有效的实体瘤治疗。