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Updated: Jan 10, 2026
A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
STING activation reshapes the tumor microenvironment leading to tumor regression in osteosarcoma
Abstract:
Osteosarcomas are characterized by a high degree of aneuploidy, chromothripsis and micronuclei, yet these tumors typically have an immunosuppressive, macrophage-rich, T-cell depleted tumor microenvironment. cGAS-STING dysregulation is a possible mechanism by which immune activation in response to tumor genomic instability could be repressed. We identified almost universal repression of cGAS or STING in human osteosarcomas. However, a STING-activation gene signature was predictive of survival in osteosarcoma patients suggesting potential for activation of this pathway in the osteosarcoma tumor microenvironment. Indeed, in immunocompetent osteosarcoma models, systemic STING agonism led to complete regression and induced lasting immunologic memory. Host STING activation is sufficient to promote this anti-tumor immunity even in the absence of tumor STING. These results nominate the cGAS-STING pathway as an important therapeutic target in osteosarcoma, a disease in which no new curative therapies have been developed in the last 40 years.
Insights
Osteosarcomas often evade immune responses due to cGAS-STING pathway repression. Activating STING in hosts can overcome this, leading to tumor regression and durable immunity, suggesting STING as a therapeutic target.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Osteosarcomas exhibit significant genomic instability but possess an immunosuppressive tumor microenvironment.
- The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is crucial for immune activation against genomic instability.
- Dysregulation of the cGAS-STING pathway may contribute to immune evasion in osteosarcoma.
Purpose of the Study:
- To investigate the role of the cGAS-STING pathway in osteosarcoma immunity.
- To explore the therapeutic potential of STING activation in osteosarcoma.
Main Methods:
- Analysis of cGAS and STING expression in human osteosarcoma samples.
- Correlation of STING activation gene signatures with patient survival.
- Evaluation of systemic STING agonism in immunocompetent osteosarcoma models.
Main Results:
- Near-universal repression of cGAS or STING was observed in human osteosarcomas.
- A STING-activation gene signature predicted better survival in osteosarcoma patients.
- Systemic STING agonism induced complete tumor regression and lasting immunologic memory in preclinical models.
- Host STING activation conferred anti-tumor immunity independently of tumor STING expression.
Conclusions:
- The cGAS-STING pathway is frequently repressed in osteosarcoma, contributing to immune evasion.
- Activating the host STING pathway is a promising therapeutic strategy for osteosarcoma.
- Targeting the cGAS-STING pathway offers a potential new avenue for treating osteosarcoma, a disease with limited therapeutic advancements.
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