HO-1 impairs the efficacy of radiotherapy by redistributing cGAS and STING in tumors
Related Experiment Video
Updated: Jun 6, 2025
Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model
Published on: June 4, 2017
Chuqing Zhang1,2, Zhenji Deng1,2, Jiawei Wu1,3
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer.
Abstract:
Type I IFNs (IFN-Is) induced by radiotherapy (RT) are critical for its efficacy, while the mechanism by which tumor cells inhibit IFN-I production remains largely unsolved. By an unbiased CRISPR screen, we identified hemeoxygenase 1 (HO-1) as an RT-related regulator of IFN-I production. Mechanistically, the ER-anchored, full-length HO-1 disrupted stimulator of IFN genes (STING) polymerization and subsequent coat protein complex II-mediated (COPII-mediated) ER-Golgi transportation, leading to hampered activation of downstream signaling. This process was exacerbated by the upregulation of HO-1 expression under RT. Importantly, RT also induced HO-1 cleavage. Cleaved HO-1 underwent nuclear translocation, interacted with cyclic GMP-AMP synthase (cGAS), and inhibited its nuclear export upon irradiation, leading to suppressed 2'3'-cyclic GMP-AMP (cGAMP) production. Furthermore, we revealed that HO-1 inhibitors could enhance local and distant tumor control of RT in vivo. Clinically, higher HO-1 expression was associated with a poorer prognosis and earlier tumor relapse after RT in multiple types of patient tumors. Collectively, through comprehensive inhibition of the cGAS/STING pathway, HO-1 strongly inhibited RT-induced IFN-I production, and targeting HO-1 was shown to be a promising RT-sensitizing therapeutic strategy.
Insights
Radiotherapy (RT) efficacy relies on Type I interferons (IFN-Is), but tumors can suppress them. Hemeoxygenase 1 (HO-1) inhibits IFN-I production by disrupting the cGAS/STING pathway, offering a target to enhance RT effectiveness.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Type I interferons (IFN-Is) are crucial for radiotherapy (RT) efficacy.
- Tumor cells employ mechanisms to inhibit IFN-I production, limiting RT effectiveness.
- The precise molecular pathways by which tumors suppress IFN-I remain largely unknown.
Purpose of the Study:
- To identify novel regulators of IFN-I production in response to RT.
- To elucidate the mechanism by which tumor cells inhibit IFN-I production.
- To evaluate the therapeutic potential of targeting identified regulators to enhance RT efficacy.
Main Methods:
- Unbiased CRISPR screening to identify RT-related regulators of IFN-I production.
- Investigation of hemeoxygenase 1 (HO-1) function using molecular and cellular assays.
- In vivo studies assessing the impact of HO-1 inhibition on RT efficacy.
- Clinical correlation analysis of HO-1 expression with patient prognosis.
Main Results:
- Hemeoxygenase 1 (HO-1) was identified as a key inhibitor of RT-induced IFN-I production.
- HO-1 disrupts the cGAS/STING pathway by inhibiting STING polymerization and cGAMP production.
- HO-1 expression is upregulated by RT, and its inhibition enhances local and distant tumor control.
- High HO-1 expression correlates with poorer prognosis and earlier relapse in cancer patients treated with RT.
Conclusions:
- HO-1 comprehensively inhibits the cGAS/STING pathway, suppressing RT-induced IFN-I production.
- Targeting HO-1 represents a promising strategy to sensitize tumors to radiotherapy.
- HO-1 inhibition can improve therapeutic outcomes in patients undergoing RT.
Related Concept Videos
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...