Targeting mitotic regulators in cancer as a strategy to enhance immune recognition.
Gregorczyk M., Parkes EE.
Eukaryotic DNA has evolved to be enclosed within the nucleus to protect the cellular genome from autoinflammatory responses driven by the immunogenic nature of cytoplasmic DNA. Cyclic GMP-AMP Synthase (cGAS) is the cytoplasmic dsDNA sensor, which upon activation of Stimulator of Interferon Genes (STING), mediates production of pro-inflammatory interferons (IFNs) and interferon stimulated genes (ISGs). However, although this pathway is crucial in detection of viral and microbial genetic material, cytoplasmic DNA is not always of foreign origin. It is now recognised that specifically in genomic instability, a hallmark of cancer, extranuclear material in the form of micronuclei (MN) can be generated as a result of unresolved DNA lesions during mitosis. Activation of cGAS-STING in cancer has been shown to regulate numerous tumour-immune interactions such as acquisition of 'immunologically hot' phenotype which stimulates immune-mediated elimination of transformed cells. Nonetheless, a significant percentage of poorly prognostic cancers is 'immunologically cold'. As this state has been linked with low proportion of tumour-infiltrating lymphocytes (TILs), improving immunogenicity of cold tumours could be clinically relevant by exhibiting synergy with immunotherapy. This review aims to present how inhibition of vital mitotic regulators could provoke cGAS-STING response in cancer and improve the efficacy of current immunotherapy regimens.