cGAS-STING signaling in acute myeloid leukemia: biology, pathophysiology and therapeutic implications.
The 'cyclic GMP-AMP synthase-Stimulator of interferon genes' (cGAS-STING) pathway is a key component of the innate immune machinery, that detects the presence of cytosolic dsDNA and initiates type I interferon-driven inflammation, resulting in downstream immune responses. In cancer, aberrant activation or suppression of this signaling pathway connects genomic instability with immune surveillance, causing context-dependent outcomes that can either augment antitumor immunity or promote tumor progression. This paradox can be exemplified using acute myeloid leukemia (AML), a genetically and clinically heterogeneous hematologic malignancy with poor long-term survival, as a model disease. Emerging evidence indicates that cGAS-STING signaling plays multifaceted roles in AML pathogenesis, influencing leukemic cell survival, stemness, inflammatory signaling, and interactions with the immune microenvironment. Genetic and epigenetic alterations common in AML engage the cGAS-STING axis to drive chronic inflammatory states, clonal expansion, and leukemic transformation, while acute or therapeutic activation of STING can improve anti-leukemic immunity. Pharmacologic STING activation promotes dendritic cell maturation, type I interferon production, and cytotoxic T cell and NK cell responses, and can synergize with hypomethylating agents, PARP inhibitors, immune checkpoint blockade, and nanoparticle-based delivery systems. This review highlights current understanding of cGAS-STING biology, its contentious roles in cancer, and its specific functions in AML, highlighting therapeutic opportunities, caveats and challenges. We discuss how the delicate balance between acute and chronic STING signaling in the setting of underlying genetic regulation and immune landscape can play critical role in determining clinical outcome, positioning cGAS-STING as a promising therapeutic target and biomarker of sterile inflammation in AML. Teaser Abstract: In this review article, we have discussed how the delicate balance between acute and chronic STING signaling in the setting of underlying genetic regulation and immune landscape can play critical role in determining clinical outcome, positioning cGAS-STING as a promising therapeutic target and biomarker of sterile inflammation in acute myeloid leukemia.