Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, P.R. China.
TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, P.R. China.
Biomater Sci. 2021 Nov 23;9(23):8019-8031. doi: 10.1039/d1bm01409a.
Nanomedicine enabled cancer combination immunotherapy not only sufficiently activates the host immune system, but also reprograms the immunosuppressive microenvironment, representing a new generation approach to treat cancer. Herein, we demonstrated a targeted photo- and immune-active nanoplatform termed NLG919@HA-Ce6 to simultaneously elicit efficient immunogenic cell death (ICD) using the photosensitizer Ce6 and modulate the tryptophan metabolic pathway using an indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 for the combined photodynamic therapy (PDT) and checkpoint blockade immunotherapy. Against the triple-negative and poorly immunogenic 4T1 breast cancer model, the stable spherical nanomicelle NLG919@HA-Ce6 selectively killed tumour cells the toxic singlet oxygen upon laser excitation, thus triggering a potent antitumor immune response, as seen the obvious CRT exposure, ATP release, dendritic cell maturation, . Meanwhile, the IDO1-mediated immunosuppression was effectively reprogrammed to an immunostimulatory phenotype, which was accompanied by an enhanced cytotoxic T cell response as well as reduced Treg infiltration in tumour bed. Ultimately, the 4T1 tumour was synergistically suppressed by NLG919@HA-Ce6 due to the outcome of focused PDT, obvious ICD post PDT and IDO1 blockade. This study suggests the promise of NLG919@HA-Ce6 as an alternative simple, stimulative and targeted nanoagent to enable the whole-body photo-immune therapy against "immune cold" cancer.
纳米医学使癌症联合免疫疗法不仅能够充分激活宿主免疫系统，还能够重新编程免疫抑制微环境，代表了一种治疗癌症的新一代方法。在此，我们展示了一种名为 NLG919@HA-Ce6 的靶向光和免疫活性纳米平台，该平台使用光敏剂 Ce6 引发有效的免疫原性细胞死亡（ICD），并使用吲哚胺 2,3-双加氧酶（IDO）抑制剂 NLG919 调节色氨酸代谢途径，用于联合光动力治疗（PDT）和检查点封锁免疫治疗。针对三阴性和免疫原性差的 4T1 乳腺癌模型，稳定的球形纳米胶束 NLG919@HA-Ce6 选择性地杀死肿瘤细胞，激光激发时产生有毒的单线态氧，从而引发强烈的抗肿瘤免疫反应，明显观察到 CRT 暴露、ATP 释放、树突状细胞成熟等现象。同时，IDO1 介导的免疫抑制被有效重编程为免疫刺激表型，这伴随着细胞毒性 T 细胞反应的增强和肿瘤床中 Treg 浸润的减少。最终，由于聚焦 PDT 的结果、明显的 PDT 后 ICD 和 IDO1 阻断，NLG919@HA-Ce6 协同抑制了 4T1 肿瘤。这项研究表明，NLG919@HA-Ce6 作为一种替代的简单、刺激和靶向纳米制剂，有望实现全身光免疫治疗“免疫冷”癌症。
