金纳米粒通过自噬调控肿瘤相关巨噬细胞表型转化的研究

As an important part of the tumor microenvironment, tumor associated macrophages (TAMs) can show M2 phenotype with pro-tumor functionality, as well as M1 phenotype with anti-tumor functionality. It has important implications for cancer therapy to induce the transformation of TAMs from M2 to M1 phenotype. Due to preferentially taken up by M2 macrophages, gold nanoparticles have unique advantages to target TAMs. Our previous studies have found that gold nanoparticles could increase the expression of TNF-α and iNOS and decrease the expression of Arg-1, Mg1 and IL-10, which suggested that gold nanoparticles could induce the transformation of TAMs from M2 to M1 phenotype. Autophagy is a highly conserved catabolic process that could regulate the phenotypic transformation of TAMs. It has been also reported that gold nanoparticles could modulate autophagy. Therefore, we speculate that the effect of gold nanoparticles on phenotypic transformation of TAMs may be mediated by autophagy. This project will prepare and characterize gold nanoparticles firstly and then validate the effect of gold nanoparticles on autophagy and phenotypic transformation of TAMs. Lastly we will confirm phenotypic transformation of TAMs induced by gold nanoparticles is regulated by autophagy at the cellular and whole animal level. The results will reveal the effect of gold nanoparticles on phenotypic transformation of TAMs, clarify the mechanism and provide a theoretical basis for the application of gold nanoparticles in tumor therapy.

肿瘤相关巨噬细胞（TAMs）是肿瘤微环境的重要组成部分，诱导TAMs由促肿瘤的M2型向抗肿瘤的M1型转化对于肿瘤治疗具有重要意义。金纳米粒由于易被M2型巨噬细胞摄取，因此在针对TAMs的靶向治疗中具有独特的优势。我们前期研究发现金纳米粒能够增加TNF-α和iNOS的表达，降低Arg-1、Mg1和IL-10的表达，这提示我们金纳米粒能够诱导TAMs由M2向M1表型转化。自噬是一种高度保守的分解代谢过程，能够调控TAMs的表型转化。研究发现金纳米粒对自噬也具有调控作用，因此，我们推测金纳米粒可能通过自噬来调控TAMs表型转化。本项目拟首先制备并表征金纳米粒，然后确证金纳米粒对TAMs表型转化及自噬的影响，最后从细胞和整体动物水平证实金纳米粒通过自噬调控TAMs表型转化。研究结果可以揭示金纳米粒对TAMs表型转化的影响，阐明调控TAMs表型转化的作用机制，为应用金纳米粒进行肿瘤治疗提供理论依据。

肿瘤相关巨噬细胞（TAMs）是肿瘤微环境的重要组成部分，也是肿瘤治疗的重要靶点。巨噬细胞是免疫细胞，在一定的刺激下会向不同方向极化，分别为M1和M2表型。大多数TAMs表现为M2表型，可显著促进肿瘤进展。因此，抑制TAMs的M2表型极化可以有效发挥抗肿瘤作用。在本研究中，我们讨论了聚乙二醇化金纳米粒（PEG-AuNPs）对TAMs表型极化的影响和潜在机制。结果发现，PEG-AuNPs可以抑制TAMs的M2表型极化，引发抗肿瘤免疫治疗作用，抑制小鼠皮下肿瘤生长。进一步研究发现，PEG-AuNPs通过碱化溶酶体和增加溶酶体膜通透性抑制溶酶体的功能，从而抑制自噬溶酶体的形成，造成自噬流的阻滞。此外，TAMs在自噬激活后易于向M2表型极化，而抑制自噬流可以降低TAMs的M2表型极化。我们的研究结果揭示了PEG-AuNPs诱导抗肿瘤免疫治疗作用的潜在机制，即PEG-AuNPs通过诱导溶酶体功能障碍和抑制自噬流来降低TAMs的M2表型极化。本研究阐明了PEG-AuNPs对TAMs表型极化的生物学效应，并为利用纳米材料的内在免疫调节能力进行有效的肿瘤治疗提供了理论依据。