DNA sensing in cancer: Pro-tumour and anti-tumour functions of cGAS-STING signalling

Area of Science:

• Immunology
• Molecular Biology
• Cancer Biology

Background:

• The cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING) pathway acts as a crucial DNA sensor, detecting cytosolic DNA indicative of infection or damage.
• In cancer, persistent DNA damage, chromosomal instability, and therapies like radio- or chemotherapy can activate cGAS-STING signalling in cancer cells and the tumour microenvironment (TME).
• This activation leads to type I interferon production, potentially enhancing immune cell infiltration in 'hot' tumours responsive to immunotherapy.

Approach:

• This mini-review explores the dual role of cGAS-STING signalling within the TME.
• It examines how STING activation influences local immune cell populations and the impact of type I interferons and cyclic GMP-AMP (cGAMP).
• The review investigates downstream signalling cascades, including chronic interferon signalling, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and inflammatory cytokine production.

Key Points:

• cGAS-STING signalling can elicit both anti-tumour and pro-tumour responses depending on the cellular context within the TME.
• Tumours have evolved sophisticated mechanisms to evade or co-opt the cGAS-STING pathway for their own advantage.
• STING signalling downstream effects include chronic interferon production and NF-κB activation, potentially driving pro-tumour inflammation.

Conclusions:

• A comprehensive understanding of DNA sensing by cGAS-STING in various cellular contexts is essential for therapeutic exploitation.
• Harnessing the anti-tumour functions of STING signalling requires nuanced strategies that consider its complex roles in the TME.
• Further research into the intricate interplay between cGAS-STING, immune cells, and tumour progression is critical for developing effective cancer immunotherapies.