Department of Chemical and Biomolecular Engineering Korea Advanced Institute of Science and Technology (KAIST) Daejeon 34141 Republic of Korea.
Department of Bioengineering, College of Engineering Hanyang University Seoul 04763 Republic of Korea.
Adv Sci (Weinh). 2021 Feb 1;8(7):2001308. doi: 10.1002/advs.202001308. eCollection 2021 Apr.
Immunogenic cell death (ICD) is distinguished by the release of tumor-associated antigens (TAAs) and danger-associated molecular patterns (DAMPs). This cell death has been studied in the field of cancer immunotherapy due to the ability of ICD to induce antitumor immunity. Herein, endoplasmic reticulum (ER) stress-mediated ICD inducing fluorinated mitochondria-disrupting helical polypeptides (MDHPs) are reported. The fluorination of the polypeptide provides a high helical structure and potent anticancer ability. This helical polypeptide destabilizes the mitochondrial outer membrane, leading to the overproduction of intracellular reactive oxygen species (ROS) and apoptosis. In addition, this oxidative stress triggers ER stress-mediated ICD. The in vivo results show that cotreatment of fluorinated MDHP and antiprogrammed death-ligand 1 antibodies (PD-L1) significantly regresses tumor growth and prevents metastasis to the lungs by activating the cytotoxic T cell response and alleviating the immunosuppressive tumor microenvironment. These results indicate that fluorinated MDHP synergizes with the immune checkpoint blockade therapy to eliminate established tumors and to elicit antitumor immune responses.
免疫原性细胞死亡（ICD）的特征是释放肿瘤相关抗原（TAA）和危险相关分子模式（DAMP）。由于 ICD 能够诱导抗肿瘤免疫，因此在癌症免疫治疗领域对其进行了研究。本文报道了内质网（ER）应激介导的 ICD 诱导的氟化线粒体破坏螺旋多肽（MDHPs）。多肽的氟化提供了高螺旋结构和强大的抗癌能力。这种螺旋多肽破坏了线粒体的外膜，导致细胞内活性氧（ROS）的过度产生和细胞凋亡。此外，这种氧化应激会引发 ER 应激介导的 ICD。体内结果表明，氟化 MDHP 与抗程序性死亡配体 1 抗体（PD-L1）联合治疗可通过激活细胞毒性 T 细胞反应和减轻免疫抑制性肿瘤微环境，显著抑制肿瘤生长并防止转移到肺部。这些结果表明，氟化 MDHP 与免疫检查点阻断疗法协同作用，以消除已建立的肿瘤并引发抗肿瘤免疫反应。
