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Targeting mitotic regulators in cancer as a strategy to enhance immune recognition

Mateusz Gregorczyk1, Eileen E Parkes1

  • 1Oxford Centre for Immuno-Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom.

DNA Repair
|October 23, 2023
PubMed

Insights

In cancer, inhibiting cell division regulators can trigger the cGAS-STING pathway. This approach may enhance anti-tumour immunity and improve immunotherapy effectiveness for cold tumors.

Area of Science:

  • Cellular Biology
  • Immunology
  • Cancer Biology

Background:

  • Eukaryotic DNA is protected within the nucleus to prevent cytoplasmic DNA from triggering autoinflammatory responses.
  • The cyclic GMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway detects cytoplasmic DNA, producing interferons (IFNs) and interferon-stimulated genes (ISGs).
  • Genomic instability in cancer can lead to extranuclear DNA in micronuclei (MN), activating the cGAS-STING pathway and influencing anti-tumour immunity.

Approach:

  • This review explores how inhibiting key mitotic regulators can induce a cGAS-STING response in cancer cells.
  • The study examines the potential of this strategy to overcome the 'immunologically cold' tumor phenotype.
  • Investigating the synergy between mitotic inhibition, cGAS-STING activation, and current immunotherapy regimens.

Key Points:

  • Cytoplasmic DNA, particularly from micronuclei in cancer, can activate the cGAS-STING pathway.
  • cGAS-STING activation contributes to an 'immunologically hot' tumor phenotype, promoting immune-mediated elimination.
  • Many poorly prognostic cancers are 'immunologically cold' due to low tumour-infiltrating lymphocytes (TILs).

Conclusions:

  • Targeting mitotic regulators may be a viable strategy to activate the cGAS-STING pathway in immunologically cold tumors.
  • Enhancing tumor immunogenicity through cGAS-STING activation could improve responses to immunotherapy.
  • This approach holds potential for synergistic effects with existing cancer immunotherapies.
Keywords:
Anti-mitoticChromosomal instabilityImmunotherapyMicronucleiTumor microenvironment

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