2. Academic Validation
  3. LAMTOR1 ablation impedes cGAS degradation caused by chemotherapy and promotes antitumor immunity

LAMTOR1 ablation impedes cGAS degradation caused by chemotherapy and promotes antitumor immunity

  • Proc Natl Acad Sci U S A. 2024 Oct 8;121(41):e2320591121. doi: 10.1073/pnas.2320591121.
Juntao Bie # 1 2,  Yutong Li # 1,  Chen Song 1,  Qiaoyou Weng 1 3,  Long Zhao 4,  Li Su 5,  Zhongwei Zhao 3,  Yingjiang Ye 4,  Zhanlong Shen 4,  Jiansong Ji 3,  Jianyuan Luo 1 2 6
Affiliations

Affiliations

  • 1 Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 2 Medical Innovation Center (Taizhou) of Peking University, Taizhou 225316, China.
  • 3 Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China.
  • 4 Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing 100044, China.
  • 5 Peking University Medical and Health Analysis Center, Beijing 100191, China.
  • 6 Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • # Contributed equally.
PMID: 39361643 DOI: 10.1073/pnas.2320591121
Abstract

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 degradation of cGAS, a potent double-strand DNA (dsDNA) sensor, by lysosomes. 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.

Keywords

LAMTOR1; cGAS; chemotherapy; lysosomal degradation; tumor immunity.

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