Recent progress in cGAS–STING agonist design and mechanisms of cancer immune modulation

Abstract

The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signalling pathway is a crucial modulator of innate immunity and an important target for next-generation cancer immunotherapy. Numerous cGAS–STING agonists have been developed and evaluated for their ability to promote anti-tumour immune responses. Cyclic dinucleotides (CDNs) are the most widely employed natural STING agonists; however, poor membrane permeability and enzymatic instability have motivated the development of non-CDN small-molecule agonists, including organic scaffolds and metal-based complexes with improved stability and tunable physicochemical properties. Additionally, nanomaterials that incorporate metal complexes with or without STING agonists have recently emerged as promising platforms for achieving robust therapeutic effects, facilitating targeted delivery, controlled release, and integration with other treatment modalities such as photodynamic therapy. This review offers a comprehensive examination of advancements over the past two years in the design and development of STING modulators, including organic scaffolds, metal-based complexes, and nanomaterials that encapsulate or tether metal-based drugs. It emphasises their chemical structures and the molecular mechanisms that facilitate STING activation and discusses significant challenges while delineating future research and therapeutic development directions.