NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.
Nat Commun. 2023 Apr 19;14(1):2248. doi: 10.1038/s41467-023-38014-6.
Targeting tumour immunosuppressive microenvironment is a crucial strategy in immunotherapy. However, the critical role of the tumour lymph node (LN) immune microenvironment (TLIME) in the tumour immune homoeostasis is often ignored. Here, we present a nanoinducer, NIL-IM-Lip, that remodels the suppressed TLIME via simultaneously mobilizing T and NK cells. The temperature-sensitive NIL-IM-Lip is firstly delivered to tumours, then directed to the LNs following pH-sensitive shedding of NGR motif and MMP2-responsive release of IL-15. IR780 and 1-MT induces immunogenic cell death and suppress regulatory T cells simultaneously during photo-thermal stimulation. We demonstrate that combining NIL-IM-Lip with anti-PD-1 significantly enhances the effectiveness of T and NK cells, leading to greatly suppressed tumour growth in both hot and cold tumour models, with complete response in some instances. Our work thus highlights the critical role of TLIME in immunotherapy and provides proof of principle to combine LN targeting with immune checkpoint blockade in cancer immunotherapy.
靶向肿瘤免疫抑制微环境是免疫治疗的关键策略。然而，肿瘤淋巴结（LN）免疫微环境（TLIME）在肿瘤免疫稳态中的关键作用往往被忽视。在这里，我们提出了一种纳米诱导剂 NIL-IM-Lip，它通过同时动员 T 细胞和 NK 细胞来重塑受抑制的 TLIME。温度敏感的 NIL-IM-Lip 首先被递送到肿瘤中，然后在 NGR 基序的 pH 敏感脱落和 MMP2 响应性释放 IL-15 后被导向 LNs。IR780 和 1-MT 在光热刺激过程中同时诱导免疫原性细胞死亡和抑制调节性 T 细胞。我们证明，将 NIL-IM-Lip 与抗 PD-1 联合使用可显著增强 T 细胞和 NK 细胞的有效性，从而在热肿瘤和冷肿瘤模型中大大抑制肿瘤生长，在某些情况下可达到完全缓解。我们的工作因此强调了 TLIME 在免疫治疗中的关键作用，并为将 LN 靶向与免疫检查点阻断相结合用于癌症免疫治疗提供了原理证明。
