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LAMTOR1 ablation impedes cGAS degradation caused by chemotherapy and promotes antitumor immunity
Juntao Bie1,2, Yutong Li1, Chen Song1
1Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
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.
Insights
Chemotherapy resistance is a major hurdle in cancer treatment. This study reveals how DNA fragments degrade the cGAS sensor, offering a new therapeutic target, LAMTOR1, to enhance cancer therapy efficacy.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Chemotherapy resistance significantly limits long-term cancer treatment success.
- Understanding the molecular mechanisms of resistance is crucial for developing improved therapies.
Purpose of the Study:
- To investigate the mechanisms by which chemotherapeutic agents induce resistance.
- To identify novel regulatory pathways controlling DNA sensing and immune responses in cancer.
Main Methods:
- Investigated the role of DNA fragments in cGAS (cyclic GMP-AMP synthase) degradation.
- Analyzed the involvement of lysosomes and the LAMTOR1 protein in cGAS regulation.
- Assessed the impact of LAMTOR1 deficiency on the cGAS-STING pathway and type I interferon production.
- Evaluated the combined effects of LAMTOR1 loss with chemotherapy and immunotherapy in mouse models.
Main Results:
- Chemotherapy-induced DNA fragments promote lysosomal degradation of the DNA sensor cGAS.
- Lysosome-localized LAMTOR1 is upregulated and enhances cGAS degradation via the p62-dependent pathway.
- LAMTOR1 deficiency leads to increased cGAS levels, enhanced cGAS-STING pathway activation, and type I interferon production.
- Loss of LAMTOR1 synergizes with chemotherapy and immunotherapy to inhibit tumor growth and improve survival by increasing T lymphocyte infiltration.
Conclusions:
- The study uncovers a novel mechanism regulating cGAS protein stability through lysosomal degradation, mediated by LAMTOR1.
- Targeting LAMTOR1 presents a potential strategy to overcome chemotherapy resistance and enhance anti-tumor immunity.
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