Targeting chaperone-mediated autophagy inhibits properties of glioblastoma stem cells and restores anti-tumor immunity
Chaperone-mediated autophagy (CMA) is a selective autophagic process essential for maintaining cellular quality and responding to stress. Dysregulation of the CMA pathway is increasingly recognized in various cancers, yet the mechanisms behind CMA hyperactivation in cancer cells remain unclear. Here, we show that CMA is upregulated in patient-derived glioblastoma stem cells (GSCs), indicated by a significant increase in the lysosomal abundance of the CMA receptor, lysosome-associated membrane protein 2 A (LAMP2A). This increase results from MST4-mediated phosphorylation of LAMP2A, enhancing its stability and promoting homotrimer formation while inhibiting degradation by Cathepsin A. CMA supports GSC proliferation and self-renewal by activating mTORC1 through the selective degradation of its negative regulators, TSC1 and TSC2. Additionally, CMA is involved in epigenetic silencing of the cGAS-STING pathway, promoting tumor immune escape via lysosomal degradation of the DNA demethylase TET3. Inhibition of CMA synergizes with immune checkpoint therapy in glioblastoma models, highlighting a potential therapeutic target.
Authors
- Jun Jun Li (ORCID: https://orcid.org/0000-0001-5591-5396)
- Min Sheng (ORCID: https://orcid.org/0000-0001-5494-5075)
- Xiao Zhou (ORCID: https://orcid.org/0000-0002-5661-6707)
- Shiyuan Hong (ORCID: https://orcid.org/0000-0002-6089-5104)
- Mei Luo (ORCID: https://orcid.org/0000-0002-0183-2373)
- Tiancai Huang (ORCID: https://orcid.org/0009-0008-9436-7298)
- Qiaoxi Xia
- Xiaobing Jiang (ORCID: https://orcid.org/0000-0001-8844-0286)
- Bing Liu (ORCID: https://orcid.org/0000-0002-7313-6924)
- Weijie Li (ORCID: https://orcid.org/0000-0002-3452-3745)
- Botao Wang (ORCID: https://orcid.org/0000-0001-9437-1184)
- Simin Liu (ORCID: https://orcid.org/0000-0003-2098-3844)
- Shi‐Yuan Cheng (ORCID: https://orcid.org/0000-0003-1737-0588)
- Ziyuan Zheng (ORCID: https://orcid.org/0000-0001-5434-6582)
- Yonghua Li (ORCID: https://orcid.org/0009-0001-2394-6742)
Institutions
- Union Hospital (HK)
- Xiamen University (CN)
- University Town of Shenzhen (CN)
- Wuhan Union Hospital (CN)
- Children’s Hospital of Fudan University Xiamen Branch (CN)
- Union Hospital (CN)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-13
- DOI
- https://doi.org/10.1038/s41467-025-67119-3
- Citations
- 1
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 1.35
Funders
- National Natural Science Foundation of China
- Science, Technology and Innovation Commission of Shenzhen Municipality