Emerging cGAS-STING Agonist-Based Nanotherapeutics: Mechanistic Insights and Applications in Cancer Combination Therapy.

The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a promising target for cancer immunotherapy. Activation of the cGAS-STING pathway holds significant potential to enhance antitumor immunity. However, their efficacy remains constrained by various drug delivery and pharmacological obstacles, including poor stability, limited cellular uptake, inefficient intracellular delivery, suboptimal tumor targeting, and immunotoxicity. There is a growing focus on the design and application of nanoparticulate drug delivery systems (nano-DDSs) to improve the delivery of cGAS-STING agonists for safe, effective, and specific targeting. This review outlines the latest advancements in cGAS-STING agonist-based nanotherapeutics. First, the research background of the cGAS-STING pathway and nanotechnology is briefly outlined to emphasize the promise of STING agonist-based nanotherapeutics in cancer immunotherapy. Second, the progress in the development of cGAS-STING agonists and recent advancements in cGAS-STING agonist-based nanotherapeutics are overviewed. Moreover, the molecular mechanisms and applications of STING agonist-based combination therapies are discussed, including synergistic strategies with chemotherapy, radiotherapy, immunotherapy (e.g., immune checkpoint blockade (ICB), indoleamine 2,3-dioxygenase (IDO) inhibitor, cancer vaccine, adoptive cell therapy (ACT)), phototherapy, sonodynamic therapy (SDT), and targeted therapy. Finally, the challenges and future perspectives of STING agonist-based nanotherapeutics in clinical cancer therapy are proposed.