冷肿瘤缺乏T细胞浸润，免疫原性低，导致免疫治疗反应不足。因此，如何实现冷肿瘤向热肿瘤的转变是一个亟待解决的问题。光动力疗法可以诱导肿瘤细胞的免疫原性死亡（ICD）并激活T淋巴细胞产生肿瘤免疫反应。然而，冷肿瘤微环境中的缺氧限制了光动力疗法的有效性。因此，本文在克服上述问题的基础上构建了MET-HMME/CAT-HMME@Nlip作为功能性共递送纳米脂质体。首先，可以通过以下两种方式改善缺氧状态，一是CAT-HMME@Nlip中负载过氧化氢酶可以分解高浓度过氧化氢产生氧气，二是MET-HMME@Nlip中负载二甲双胍可以减少缺氧状态。通过抑制线粒体呼吸来消耗氧气。而随着底物氧浓度的增加，光动力治疗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，不仅能消灭原发肿瘤，还能通过免疫记忆功能抑制模拟远处肿瘤的生长。该研究为提高缺氧冷肿瘤的临床治疗效果提供了新思路，特别是对于因肿瘤细胞表面PD-L1蛋白低表达或无表达而无法从免疫治疗中获益的肿瘤。版权所有©2024。爱思唯尔有限公司

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.Copyright © 2024. Published by Elsevier B.V.