基于其诱导强烈免疫原性细胞死亡（ICD）的能力，化学动力疗法（CDT）被精心设计与免疫疗法结合，以产生协同的抗癌效果。然而，低氧癌细胞可以自适应地调节低氧诱导因子-1（HIF-1）途径，导致活性氧（ROS）-稳态和免疫抑制性肿瘤微环境。因此，ROS依赖的CDT疗效和免疫疗法大大降低，进一步降低它们的协同作用。本文报道了一种脂质体纳米制剂，同时传递Fenton催化剂叶酸铜和HIF-1抑制剂类白花丹素（ACF），用于乳腺癌治疗。通过体外和体内实验，证明了铜油酸盐启动的CDT通过抑制HIF-1-谷胱甘肽途径的ACF获得加强，从而放大ICD，以获得更好的免疫治疗效果。同时，ACF作为免疫佐剂显著降低了乳酸和腺苷含量，并下调了程序性死亡配体-1（PD-L1）的表达，从而以CDT独立的方式促进抗肿瘤免疫应答。因此，"一石"ACF充分利用了CDT和免疫疗法（两只鸟）以获得更好的治疗效果。 版权所有©2023 Elsevier B.V.出版。

Based on its ability to induce strong immunogenic cell death (ICD), chemodynamic therapy (CDT) was elaborately designed to combine with immunotherapy for a synergistic anticancer effect. However, hypoxic cancer cells can adaptively regulate hypoxia-inducible factor-1 (HIF-1) pathways, leading to a reactive oxygen species (ROS)-homeostatic and immunosuppressive tumor microenvironment. Consequently, both ROS-dependent CDT efficacy and immunotherapy are largely diminished, further lowering their synergy. Here, a liposomal nanoformulation co-delivering a Fenton catalyst copper oleate and a HIF-1 inhibitor acriflavine (ACF) was reported for breast cancer treatment. Through in vitro and in vivo experiments, copper oleate-initiated CDT was proven to be reinforced by ACF through HIF-1-glutathione pathway inhibition, thus amplifying ICD for better immunotherapeutic outcomes. Meanwhile, ACF as an immunoadjuvant significantly reduced the levels of lactate and adenosine, and downregulated the expression of programmed death ligand-1 (PD-L1), thereby promoting the antitumor immune response in a CDT-independent manner. Hence, the "one stone" ACF was fully taken advantage of to enhance CDT and immunotherapy (two birds), both of which contributed to a better therapeutic outcome.Copyright © 2023. Published by Elsevier B.V.