Current Perspectives on STING Agonists for Anticancer Drug Development

Abstract

The cyclic GMP-AMP (cGAS) synthase and stimulator of interferon genes signaling pathway plays a central role in bridging innate and adaptive immunity, particularly within the context of cancer. Activation begins when cytosolic double-stranded DNA is detected, leading to the production of cyclic GMP-AMP (cGAMP) and subsequent activation of STING. This initiates a cascade that induces the expression of type I interferons (IFN) and proinflammatory cytokines, enhancing antitumor immune responses through the stimulation of dendritic cells, cytotoxic T lymphocytes, and natural killer cells. Despite strong therapeutic potential, many currently available cyclic dinucleotide (CDN) and synthetic noncyclic dinucleotide (non-CDN) STING agonists face critical limitations. Common issues include poor pharmacokinetics, low cellular permeability, enzymatic degradation, and inadequate systemic bioavailability. In some cases, excessive immune activation has been observed, resulting in toxicity, chronic inflammation, or immunosuppressive tumor microenvironments. Furthermore, species-specific activity restricts the translational relevance of several compounds. These limitations highlight the need for the development of novel STING agonists with improved potency, selectivity, safety, and pharmacological profiles. This review presents a detailed analysis of molecular design approaches and structure–activity relationship (SAR) data for STING agonists, emphasizing their relevance in cancer therapy. A total of 60 synthetic compounds with diverse chemical scaffolds are examined to identify structural features linked to enhanced STING activation. These findings may support the discovery of novel STING-targeted molecules that could improve therapeutic outcomes in cancer treatment.