Bridging innate and adaptive tumor immunity: cGAS–STING pathway activation to potentiate immune checkpoint blockade

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is critical for innate immunity, as it detects cytoplasmic DNA and drives type I interferon signaling. Pharmacological stimulation of this pathway has been recognized as a valuable approach for cancer immunotherapy, especially when used together with immune checkpoint inhibitors (ICIs). Preclinical studies have demonstrated synergistic antitumor effects of cGAS-STING agonists and ICIs across various tumor models, while early-phase clinical trials are exploring their safety and efficacy in patients. Nonetheless, intrinsic tumor resistance, an immunosuppressive tumor microenvironment (TME), and therapy-associated immune toxicities continue to pose substantial obstacles to clinical application. In this review, we provide an overview of the present status of cGAS-STING agonists, emphasizing preclinical and clinical advances in combination therapy with ICIs, and discusses the challenges and future directions to optimize efficacy, improve safety, and expand the therapeutic potential of this strategy in oncology.