by chemotherapy and promotes antitumor immunity

• 成果类型: Article
• 署名作者: Bie, Juntao; Li, Yutong; Song, Chen; Weng, Qiaoyou; Zhao, Long; Su, Li; Zhao, Zhongwei; Ye, Yingjiang; Shen, Zhanlong; Ji, Jiansong; Luo, Jianyuan
• 署名单位: Peking University; Peking University; Wenzhou Medical University; Peking University; Peking University; Peking University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13211
• DOI: 10.1073/pnas.2320591121
• 发表日期: 2024-10-08
• 关键词: cyclic gmp-amp; sting pathway; dna-damage; cgas; cancer; lamtor1

摘要

Chemotherapy resistance remains a significant obstacle that limits the long- term efficacy of cancer therapy, necessitating further investigations into the underlying mechanisms. Here, we find that DNA fragments induced by chemotherapeutic agents trigger the Mechanically, the lysosome- localized protein LAMTOR1 is up- regulated, and the interaction between LAMTOR1 and cGAS is enhanced upon exposure to DNA fragments, boosting the accumulation and digestion of cGAS in lysosomes through the receptor protein p62. LAMTOR1 deficiency increases cGAS abundance and promotes activation of the cGAS-STING pathway, leading to subsequent production of type I interferons induced by cytosolic DNA stimulation. Loss of LAMTOR1 synergizes with immunotherapy and chemotherapy to inhibit tumor growth and prolong the survival time of tumor- bearing mice by promoting the infiltration of effective T lymphocytes. Thus, our study reveals a regulation of cGAS abundance and provides a potential strategy to overcome chemotherapy resistance by targeting LAMTOR1.