Targeting cGAS-STING signaling to overcome antibiotic-resistant bacterial infections: Challenges and opportunities

Increasing antibiotic-resistant bacterial infections pose a global public health challenge that demands therapeutic strategies beyond conventional antibiotics. The cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING) pathway is crucial to innate immune defense through cytosolic DNA detection and antimicrobial response initiation. Emerging evidence suggests that antibiotic-resistant bacteria can subvert or overactivate this pathway, leading to immune evasion and excessive inflammation. Methicillin-resistant Staphylococcus aureus, carbapenem-resistant Acinetobacter baumannii, and multidrug-resistant Mycobacterium tuberculosis exploit cGAS-STING signaling to suppress host immunity or trigger damaging hyperinflammatory responses. This highlights the dual nature of the cGAS-STING pathway in bacterial infections. STING agonists may enhance immune responses against persistent infections, and STING inhibitors can mitigate excessive inflammation caused by resistant pathogens. Targeting the cGAS-STING pathway represents a host-directed therapy that modulates host immunity rather than targeting pathogens. Understanding the interplay between cGAS-STING signaling and antibiotic resistance mechanisms is essential for developing next-generation immunotherapeutics to complement conventional antibacterial treatments.