Exploring the role of cGAS-STING-mediated inflammation in age-associated neurodegeneration and antitumor immunity

Inflammation stands as a dynamic and intricate biological process, promoting vital defence mechanisms against harmful stimuli, including infections and injuries, to drive pathogen clearance and healing. On one hand, these responses can manifest acutely and be short-lived, containing and neutralising threats. Conversely, when these responses become dysregulated and persist, leading to chronic inflammation, they drive tissue damage, adversely affecting diverse cell types and organs, and exacerbating the progression of numerous diseases. This thesis delves into the function of cGAS-STING, an evolutionarily conserved innate immune signalling pathway, in diverse inflammatory contexts, elucidating both its detrimental implications and its potential to be harnessed for protective outcomes. More specifically, this research explores the adverse facets of STING activation in the ageing process, and its potential to elicit safeguarding anti-tumour responses.The emergence of age-related aberrant and chronic inflammatory responses arises from cellular and tissue homeostasis disturbances. This is often driven by various forms of cellular damage, leading to aberrant localisation of essential cellular components, such as nucleic acids. These elements possess the inherent ability to trigger potent inflammatory responses by activating specific nucleic acid sensors, with one noteworthy being cGAS. Taking advantage of H-151, a specific inhibitor of STING, this study aims to further our understanding of the implications associated with STING signalling in the context of ageing. Our research demonstrates that age-related STING-dependent inflammatory responses manifest across diverse tissues and can be alleviated through STING inhibition. Furthermore, our investigation uncovers a critical role played by cytosolic mitochondrial self-DNA, which emerges as a potent instigator of aberrant cGAS activation in microglia cells, driving age-related neuroinflammation and ultimately contributing to cognitive decline.In a second project, a contrasting approach is adopted, aimed at activating STING signalling to enhance antitumour immune responses. The emergence of immunotherapy has revolutionised cancer treatments, yielding complete and enduring responses. This success is largely attributed to breakthroughs in checkpoint inhibitors and adoptive T cell therapies, most notably chimeric antigen receptor (CAR) T cell therapy. While these therapies have shown remarkable success against B-cell malignancies, they lack effectiveness against solid tumours. To overcome this, researchers are exploring the potential of arming T cells with immunostimulatory molecules to provoke bystander immunity, thereby broadening the scope of anti-cancer defences. This pursuit is particularly pertinent within the context of solid tumours, characterised by antigen heterogeneity. This study aims to enhance CAR-T cell therapy by harnessing the cGAS-STING axis, known for its capacity to induce type I interferons that positively impact anti-tumour immunity. Furthermore, the secreted molecule cGAMP extends its influence to neighbouring cells, facilitating the transformation of immune-depleted 'cold' into inflamed 'hot' tumour milieus, associated with improved clinical outcomes. Our study reveals that cGAMP released by engineered CAR-T cells reshapes the immune landscape, fostering acute inflammation and culminating in an escalated immune attack against established solid tumours.