2. Academic Validation
  3. Cholesterol biosynthesis induced by radiotherapy inhibits cGAS-STING activation and contributes to colorectal cancer treatment resistance

Cholesterol biosynthesis induced by radiotherapy inhibits cGAS-STING activation and contributes to colorectal cancer treatment resistance

  • Exp Mol Med. 2025 May;57(5):1089-1105. doi: 10.1038/s12276-025-01457-6.
Lijun Zhu # 1,  Zhaohui Tang # 2,  Wen Jiang # 1,  Yuwen Dong 1,  Xiaofei Li 1,  Kai Huang 2,  Tiancong Wu 3,  Lingyan Xu 4,  Wenjie Guo 5,  Yanhong Gu 6
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, The First Clinical Medical College of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Science, Nanjing University, Nanjing, China.
  • 3 Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. tiancong.wu@163.com.
  • 4 Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, The First Clinical Medical College of Nanjing Medical University, Nanjing Medical University, Nanjing, China. xulingyan1994@163.com.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Science, Nanjing University, Nanjing, China. guowj@nju.edu.cn.
  • 6 Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, The First Clinical Medical College of Nanjing Medical University, Nanjing Medical University, Nanjing, China. guyhphd@163.com.
  • # Contributed equally.
PMID: 40355720 DOI: 10.1038/s12276-025-01457-6
Abstract

Radiotherapy-induced DNA damage can lead to apoptotic cell death and trigger an anti-tumor immune response via the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which senses cytoplasmic double-stranded DNA. However, radiotherapy resistance poses a significant challenge in treating cancers, including colorectal Cancer (CRC). Understanding the mechanisms underlying this resistance is crucial for developing effective therapies. Here we report that radiotherapy enhances Cholesterol synthesis, which subsequently inhibits the cGAS-STING pathway, leading to radiotherapy resistance. Mechanistically, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) levels increase rapidly in response to radiation, resulting in increased Cholesterol synthesis. This increased Cholesterol sequesters STING in the endoplasmic reticulum, hindering its activation and downstream interferon signaling. Elevated HMGCR and Cholesterol levels correlate with poor prognosis and reduced response to radiation therapy in patients with CRC. Importantly, pharmacological inactivation of HMGCR significantly enhanced radiotherapy responsiveness in animal models, dependent on cGAS-STING signaling-mediated anti-tumor responses. Our findings reveal that radiotherapy-induced Cholesterol inhibits cGAS-STING signaling, facilitating tumor immune escape. Therefore, combining statins with radiotherapy represents a promising therapeutic strategy for treating CRC.

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