Abstract：
Cold tumors lack T cells infiltration and have low immunogenicity, resulting insufficient immunotherapy response. Therefore, how to realize the transformation from cold tumor to hot tumor is an urgent problem to be solved. Photodynamic therapy can induce immunogenic death of tumor cells (ICD) and activate T lymphocytes to produce tumor immune response. However, hypoxia in the cold tumor microenvironment limits the effectiveness of photodynamic therapy. So in this article, MET-HMME/CAT-HMME@Nlip as a functional co-delivery nanoliposomes was constructed based on overcoming the above problems. Firstly, the oxygen-deficient state could be improved by the following two ways, one is catalase loaded in CAT-HMME@Nlip can decompose high concentration hydrogen peroxide to produce oxygen, and the other is metformin loaded in MET-HMME@Nlip can decrease oxygen consumption by inhibiting of mitochondrial respiration. And then with the increase of substrate oxygen concentration, the sensitivity of photodynamic therapy can be greatly improved and the anti-tumor immune response by PDT-induced ICD can also be enhanced obviously. In addition, metformin could act as a small molecule immune checkpoint inhibitor to reduce the expression of PD-L1 on the surface of tumor cells, thereby effectively improving the specific killing ability of cytotoxic T cells to tumor cells which could not only erasing the primary tumor, but also inhibiting the growth of simulated distant tumors through the immune memory function. This study provides a new idea for improving the clinical treatment effect of hypoxic cold tumors, especially for tumors that could not benefit from immunotherapy due to low or no expression of PD-L1 protein on the surface of tumor cells.
摘要：
冷肿瘤缺乏T细胞浸润，免疫原性低，导致免疫疗法反应不足。因此,如何实现从冷肿瘤到热肿瘤的转化是一个亟待解决的问题。光动力疗法可以引诱肿瘤细胞免疫原性逝世亡(ICD)和激活T淋巴细胞产生肿瘤免疫反响。然而,冷肿瘤微环境中的缺氧限制了光动力疗法的有效性。所以在这篇文章中，基于克服上述问题,构建了作为功能性共递送纳米脂质体的MET-HMME/CAT-HMME@Nlip。首先,缺氧状态可以通过以下两种方式得到改善，一种是CAT-HMME@Nlip中负载的过氧化氢酶可以分解高浓度的过氧化氢产生氧气，另一种是在MET-HMME@Nlip中加载二甲双胍可以通过抑制线粒体呼吸来减少氧气消耗。然后随着底物氧浓度的增加，光动力疗法的敏感性可以大大提高，PDT诱导的ICD的抗肿瘤免疫反应也可以明显增强。此外,二甲双胍可以作为一种小分子免疫检查点抑制剂，降低肿瘤细胞表面PD-L1的表达，从而有效提高细胞毒性T细胞对肿瘤细胞的特异性杀伤能力,而且还通过免疫记忆功能抑制模拟远处肿瘤的生长。本研究为提高低氧冷肿瘤的临床治疗效果提供了新思路,特别是对于由于肿瘤细胞表面PD-L1蛋白的低表达或无表达而无法从免疫治疗中获益的肿瘤。
