Cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment.

Abstract

Targeting cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is a promising strategy for tumor treatment. The pattern recognition receptor cGAS identifies dsDNA and catalyzes the formation of a second messenger 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), activating the downstream interferons and pro-inflammatory cytokines through the adaptor protein STING. Notably, in tumor immune microenvironment, key components of cGAS-STING pathway are transferred among neighboring cells. The intercellular transmission under these contexts serves to sustain and amplify innate immune responses while facilitating the emergence of adaptive immunity. The membrane-based system, including extracellular vesicles transport, phagocytosis and membrane fusion transmit dsDNA, cGAMP and activated STING, enhances the immune surveillance and inflammatory responses. The membrane proteins, including a specific protein channel and intercellular gap junctions, transfer cGAMP and dsDNA, which are crucial to regulate immune responses. The ligand-receptor interactions for interferon transmission amplifies the anti-tumor response. This review elaborates on the regulatory mechanisms of cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment, explores how these mechanisms modulate immunological processes and discusses potential interventions and immunotherapeutic strategies targeting these signaling cascades.