Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.
ACS Appl Mater Interfaces. 2020 Nov 11;12(45):50734-50747. doi: 10.1021/acsami.0c14909. Epub 2020 Oct 30.
Cancer immunotherapy has been a favorable strategy for facilitating antitumor immunity. However, immune tolerance and an ultimate immunosuppressive tumor microenvironment (ITM) are primary obstacles. To achieve the goals of remodeling the ITM and promoting cancer immunotherapy, a versatile nanoparticle codelivering shikonin (SK) and PD-L1 knockdown siRNA (SK/siR-NPs) was reported. SK/siR-NPs are demonstrated to tellingly induce the immunogenic cell death (ICD) of tumor cells, leading to increased dendritic cell maturation. Moreover, SK/siR-NPs can cause an efficacious inhibition of PD-L1, leading to enhanced cytotoxic T lymphocyte response to tumor cells. Most importantly, SK/siR-NPs can restrain lactate production via the downregulation of pyruvate kinase-M2 (PKM2) and eventually repolarize tumor associated macrophages (TAMs) from the M2-subtype to M1-subtype states. Meanwhile, SK/siR-NPs suppress regulatory T lymphocytes to fight with the ITM. Overall, the developed co-delivery system presents a significant potential for cancer immunotherapy through simultaneously inducing ICD, repolarizing M2-TAMs, and relieving PD-L1 pathway-regulated immune tolerance.
癌症免疫疗法一直是促进抗肿瘤免疫的有利策略。然而，免疫耐受和最终的免疫抑制肿瘤微环境（ITM）是主要障碍。为了实现重塑 ITM 和促进癌症免疫治疗的目标，报道了一种多功能纳米粒子共递给药紫草素（SK）和 PD-L1 敲低 siRNA（SK/siR-NPs）。研究表明，SK/siR-NPs 能显著诱导肿瘤细胞的免疫原性细胞死亡（ICD），导致树突状细胞成熟增加。此外，SK/siR-NPs 可以有效地抑制 PD-L1，增强细胞毒性 T 淋巴细胞对肿瘤细胞的反应。最重要的是，SK/siR-NPs 可以通过下调丙酮酸激酶-M2（PKM2）来抑制乳酸的产生，最终将肿瘤相关巨噬细胞（TAMs）从 M2 亚型重极化到 M1 亚型。同时，SK/siR-NPs 抑制调节性 T 淋巴细胞与 ITM 作斗争。总的来说，所开发的共递药系统通过同时诱导 ICD、重极化 M2-TAMs 和缓解 PD-L1 通路调节的免疫耐受，为癌症免疫治疗提供了巨大的潜力。
