cGAS-STING Signalling in the tumour microenvironment: Implications for immune surveillance and therapeutic strategies

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway links cytosolic DNA sensing to type I interferon production and inflammatory signalling, making it central to innate immunity. In addition to defending against pathogens, it shapes the tumour microenvironment by regulating immune surveillance, antitumour activity, and tumour progression. Short-term cGAS-STING activation enhances dendritic cell maturation, antigen presentation, macrophage polarisation, and cytotoxic lymphocyte recruitment. However, prolonged activation shifts the TME into an immunosuppressive state by inducing NF-κB-mediated inflammation, expanding regulatory T cells, increasing myeloid-derived suppressor cell accumulation, and elevating immune checkpoint expression. Crosstalk among the STAT3, TGF-β, and autophagy pathways further impacts angiogenesis, fibrosis, and metastasis. Additionally, metabolic stress, mitochondrial DNA (mtDNA) release, and epigenetic silencing of pathway components under hypoxic or chromosomally unstable conditions modify STING responsiveness, ultimately affecting therapeutic outcomes. Pharmacological activation using cyclic dinucleotides (CDN) STING agonists (ADU-S100 and MK-1454) and non-CDN STING agonists (diABZI and MSA-2), as well as MPS1 inhibitors (CFI-402257, BAY-1217389, and CC-671), has effectively triggered strong type I interferon responses and caused tumour regression in preclinical and clinical trials. When combined with radiotherapy, PARP inhibitors, or immune checkpoint blockers, these agents exhibit enhanced synergy but are constrained by tumour heterogeneity and context-dependent toxicity. Here, we reviewed the complexity of the cGAS-STING and its potential as a double-edged sword in cancer treatment, underscoring the need for strict strategies to harness this pathway while enhancing antitumour immunity and mitigating pro-tumorigenic effects.