Targeting the cGAS-STING Pathway for Cancer Immunotherapy: From Small-Molecule Agonists to Advanced Nanomaterials

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has emerged as a pivotal mediator of antitumor immunity, bridging innate and adaptive immune responses through its ability to sense cytoplasmic DNA and orchestrate cytokine production. This review comprehensively explores recent advancements in targeting this pathway for cancer immunotherapy, focusing on two key strategies: small-molecule agonists and nanomaterial-based therapeutics. Small-molecule agonists, including cyclic dinucleotide (CDN) derivatives and non-nucleotide compounds, have been engineered to overcome limitations such as enzymatic degradation and poor bioavailability. Candidates such as ADU-S100 and MSA-2 demonstrate enhanced STING activation and clinical potential. Concurrently, innovative nanoplatforms, which incorporate both inorganic materials, such as those based on manganese, zinc, or arsenic, and organic carriers, like liposomes, polymers, exosomes, and ferritin, leverage tumor microenvironment (TME)-responsive designs to amplify cGAS-STING signaling. These nanotherapeutics synergize DNA damage induction, immunogenic cell death, and immune checkpoint blockade to convert immunologically "cold" tumors into "hot" phenotypes. Despite progress, challenges persist in balancing pathway activation efficacy with systemic toxicity, optimizing systemic delivery for metastatic tumors, and ensuring long-term biocompatibility. Future directions emphasize the development of smart nanocarriers with spatiotemporal control, biomarker-driven patient stratification, and combinatorial regimens that integrate epigenetic or metabolic modulators. This review underscores the transformative potential of cGAS-STING-targeted therapies while outlining critical hurdles and interdisciplinary strategies to advance precision cancer immunotherapy.