Autophagy inhibition sensitizes radiotherapy responses in high-grade mutant IDH1 glioma
Mutant isocitrate dehydrogenase 1 (mIDH1) catalyzes 2-hydroxyglutarate (2HG) production which leads to epigenetic reprogramming in astrocytomas with tumor protein p53 (TP53)/α-thalassemia/mental retardation, X-linked (ATRX) loss. RNA-sequencing, single-cell RNA-sequencing, and Chromatin Immunoprecipitation sequencing (ChIP-seq) followed by bioinformatics analysis shows that human and mouse mIDH1 gliomas exhibit downregulated gene ontologies (GOs) related to mitochondrial metabolism and upregulated autophagy-related GOs. Decreased mitochondrial metabolism is accompanied by decreased glycolysis, rendering autophagy as a source of energy in mIDH1 gliomas. Mutant IDH1 glioma cells exhibit increased expression of autophagy-related proteins and enhanced microtubule-associated protein 1 light chain 3 (LC3) I/II conversion, indicating augmented autophagy. Inhibiting autophagy in vivo by administration of synthetic protein nanoparticles (SPNPs) encapsulating autophagy related gene 7 (ATG7) silencing RNA sensitizes mIDH1 glioma cells to radiation, resulting in tumor regression, long-term survival, and immunological memory. This work uncovers autophagy as a critical pathway for survival in mIDH1 gliomas and its inhibition elicits radiosensitivity in vitro in human and mouse mIDH1 glioma cells, and in vivo in mIDH1 models.
Authors
- Peter Sajjakulnukit (ORCID: https://orcid.org/0000-0002-8556-7481)
- Stephen V. Carney (ORCID: https://orcid.org/0000-0001-7786-5158)
- Ziwen Zhu (ORCID: https://orcid.org/0000-0002-6681-9153)
- Andrea Comba (ORCID: https://orcid.org/0000-0002-3398-5753)
- Brandon L. McClellan (ORCID: https://orcid.org/0000-0001-8505-3854)
- Jorge A. Peña Agudelo (ORCID: https://orcid.org/0000-0003-3470-7824)
- Maureen A. Sartor (ORCID: https://orcid.org/0000-0001-6155-5702)
- Joshua D. Welch (ORCID: https://orcid.org/0000-0002-5869-2391)
- Julio Zelaya
- Kaushik Banerjee (ORCID: https://orcid.org/0000-0002-9903-4192)
- Shi‐Yuan Cheng (ORCID: https://orcid.org/0000-0003-1737-0588)
- Zeribe C. Nwosu (ORCID: https://orcid.org/0000-0003-1641-2045)
- Mats Ljungman (ORCID: https://orcid.org/0000-0003-1553-6695)
- Mahmoud S. Alghamri (ORCID: https://orcid.org/0000-0002-8018-7674)
- Joerg Lahann (ORCID: https://orcid.org/0000-0002-3334-2053)
- Padma Kadiyala (ORCID: https://orcid.org/0000-0002-3273-9905)
- Pedro R. Löwenstein (ORCID: https://orcid.org/0000-0002-8427-4409)
- María G. Castro (ORCID: https://orcid.org/0000-0003-2237-2756)
- Claire E. Tronrud (ORCID: https://orcid.org/0000-0003-4022-7384)
- Adam Klaiss
- Sadhakshi Raghuram
- Tingting Qin (ORCID: https://orcid.org/0000-0003-3810-7578)
- Ayman Taher
- Maria B. Garcia-Fabiani
- Maya R. Sheth
- Hanna S. Hong
- Costas A. Lyssiotis
- Felipe J. Núñez
- Anzar A. Mujeeb
- Ava Mauser
Institutions
- Northwestern University (US)
- University of Michigan (US)
- Michigan Medicine (US)
- Michigan Center for Translational Pathology (US)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-18
- DOI
- https://doi.org/10.1038/s41467-026-77320-7
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00