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Translational Therapeutics

The STING pathway: Therapeutic vulnerabilities in ovarian cancer

British Journal of Cancer volume 127, pages 603–611 (2022)Cite this article

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Abstract

Ovarian cancer is the leading cause of mortality due to gynecologic malignancy. The majority of women diagnosed with the most common subtype, high-grade serous ovarian carcinoma (HGSC), develop resistance to conventional therapies despite initial response to treatment. HGSC tumors displaying DNA damage repair (DDR) gene deficiency and high chromosomal instability mainly associate with higher cytotoxic immune cell infiltration and expression of genes associated with these immune pathways. Despite the high level of immune infiltration observed, the majority of patients with HGSC have not benefited from immunomodulatory treatments as the mechanistic basis of this infiltration is unclear. This lack of response can be primarily attributed to heterogeneity at the levels of both cancer cell genetic alterations and the tumour immune microenvironment. Strategies to enhance anti-tumour immunity have been investigated in ovarian cancer, of which interferon activating therapies present as an attractive option. Of the several type I interferon (IFN-1) stimulating therapies, exogenously activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is emerging as a promising avenue. Herein, we highlight our current understanding of how constitutive and induced cGAS-STING pathway activation influences the ovarian tumour microenvironment. We further elaborate on the links between the genomic alterations prevalent in ovarian tumours and how the resultant immune phenotypes can make them more susceptible to exogenous STING pathway activation and potentiate immune-mediated killing of cancer cells. The therapeutic potential of cGAS-STING pathway activation in ovarian cancer and factors implicating treatment outcomes are discussed, providing a rationale for future combinatorial treatment approaches on the backbone of chemotherapy.

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Fig. 1: cGAS-STING pathway.
Fig. 2: Variable immune cell infiltration patterns within multiple tumours from a single patient.
Fig. 3: Factors altering STING pathway activation in ovarian cancer for potential therapeutic combinations.

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Acknowledgements

This work was supported by funding from the Canadian Institutes for Health Research and the Ontario Ministry of Research, Innovation, and Science Early Researcher Award to MK. Fellowship support to NS was provided by the Franklin Bracken Fellowship, Queen’s University, and the Canada Graduate Scholarship program.

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Authors and Affiliations

  1. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Noor Shakfa, Deyang Li, Juliette Wilson-Sanchez & Madhuri Koti

  2. Queen’s Cancer Research Institute, Queen’s University, Kingston, ON, Canada

    Noor Shakfa, Deyang Li, Juliette Wilson-Sanchez & Madhuri Koti

  3. Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada

    Sarah Nersesian

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  1. Noor Shakfa
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MK conceived the manuscript. NS reviewed the literature, drafted the papre and created the illustrations. DL contributed to writing the manuscript. MK, NS, DL, SN, and JWS helped with editing and revising the manuscript.

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Correspondence to Madhuri Koti.

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Shakfa, N., Li, D., Nersesian, S. et al. The STING pathway: Therapeutic vulnerabilities in ovarian cancer. Br J Cancer 127, 603–611 (2022). https://doi.org/10.1038/s41416-022-01797-4

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