Cancer Center and.
Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
JCI Insight. 2021 Dec 8;6(23):e146334. doi: 10.1172/jci.insight.146334.
Cancer cell radioresistance is the primary cause of the decreased curability of non-small cell lung cancer (NSCLC) observed in patients receiving definitive radiotherapy (RT). Following RT, a set of microenvironmental stress responses is triggered, including cell senescence. However, cell senescence is often ignored in designing effective strategies to resolve cancer cell radioresistance. Herein, we identify the senescence-like characteristics of cancer-associated fibroblasts (CAFs) after RT and clarify the formidable ability of senescence-like CAFs in promoting NSCLC cell proliferation and radioresistance through the JAK/STAT pathway. Specific induction of senescence-like CAF apoptosis using FOXO4-DRI, a FOXO4-p53-interfering peptide, resulted in remarkable effects on radiosensitizing NSCLC cells in vitro and in vivo. In addition, in this study, we also uncovered an obvious therapeutic effect of FOXO4-DRI on alleviating radiation-induced pulmonary fibrosis (RIPF) by targeting senescence-like fibroblasts in vivo. In conclusion, by targeting senescence, we offer a strategy that simultaneously decreases radioresistance of NSCLC and the incidence of RIPF.
癌细胞放射抵抗是导致接受根治性放疗（RT）的非小细胞肺癌（NSCLC）患者治愈率降低的主要原因。在 RT 后，会引发一系列微环境应激反应，包括细胞衰老。然而，在设计有效策略以解决癌症细胞放射抵抗时，细胞衰老通常被忽视。在此，我们在 RT 后鉴定了癌相关成纤维细胞（CAF）的衰老样特征，并通过 JAK/STAT 通路阐明了衰老样 CAF 在促进 NSCLC 细胞增殖和放射抵抗方面的强大能力。使用 FOXO4-DRI（一种 FOXO4-p53 干扰肽）特异性诱导衰老样 CAF 凋亡，可显著增强体外和体内对 NSCLC 细胞的放射增敏作用。此外，在这项研究中，我们还发现 FOXO4-DRI 通过靶向体内衰老样成纤维细胞对缓解放射性肺纤维化（RIPF）具有明显的治疗作用。总之，通过靶向衰老，我们提供了一种同时降低 NSCLC 放射抵抗和 RIPF 发生率的策略。
