Targeting cGAS-STING signaling and cell death modes in cancer and autoimmune diseases

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is an important component of innate immunity, involved in regulating various pathological conditions such as cancer, autoimmune and inflammatory diseases, microbial and parasitic infections. It also regulates various cellular physiological processes, including cytokine production, autophagy, protein synthesis, metabolism, aging, and different types of cell death. Cell death is essential for maintaining homeostasis, promoting tissue repair, and regeneration. Emerging evidence underscores the dynamic interplay between cGAS-STING signaling and cell death, highlighting their relevance in disease pathogenesis and progression. Therefore, elucidating the specific role of the cGAS-STING signaling pathway and associated cell death mechanisms in vivo is critical for targeted disease interventions. This review systematically investigates the mechanistic interactions between the cGAS-STING signaling pathway and cell death modalities, such as autophagy, necroptosis, apoptosis, pyroptosis, ferroptosis, and cuproptosis. Understanding these interactions may provide new therapeutic strategies. We particularly highlight the pathological relevance of cGAS-STING signaling pathway and cell death in human diseases, with a focus on autoimmune disorders, cancer, inflammation, and the impact of organ damage. By clarifying the molecular mechanisms linking cGAS-STING signaling pathway to various cell death modalities and their contributions to disease, we aim to provide a theoretical framework for the rational design of novel therapies targeting this pathway.