cGAS–STING signalling in triple-negative breast cancer: a functional-state framework for biomarker-guided intervention

Triple-negative breast cancer (TNBC) combines genomic instability with heterogeneous immune responses. Cyclic GMP–AMP synthase (cGAS) detects mislocalised DNA and produces cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), which activates stimulator of interferon genes (STING). The resulting response can support antigen presentation or sustain inflammatory adaptation. This review interprets these divergent effects through four non-exclusive functional states: immune-productive activation, tumour-intrinsic attenuation, chronic inflammatory rewiring and extracellular cGAMP-restricted signalling. We connect DNA accessibility, metabolic control, receptor trafficking and immune-cell responses to characteristic evidence combinations for each state. Radiation, chemotherapy, poly(ADP-ribose) polymerase (PARP) inhibition, immune checkpoint blockade (ICB), STING agonism and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibition address different constraints within this circuit. Mixed regional profiles are retained rather than forced into a single category. We distinguish baseline assignment, treatment-associated pharmacodynamics and independent clinical outcomes, and outline an adaptive research workflow. The framework offers testable explanations for conflicting pathway readouts, but requires assay standardisation and prospective validation before it can guide clinical treatment assignment.