Advances in polymer nanomaterials targeting cGAS-STING pathway for enhanced cancer immunotherapy

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has been recognized as a promising target for cancer immunotherapy. Although various STING agonists have been developed, their clinical applications are still severely impeded by various issues, such as non-specific accumulation, adverse effects, rapid clearance, etc. In recent years, the emergence of nanomaterials has profoundly revolutionized STING agonists delivery, which promote tumor-targeted delivery, boost the immunotherapeutic effects and reduce systemic toxicity of STING agonists. In particular, polymer nanomaterials possess inherent advantages including controllable structure, tunable function and degradability. These properties afford them the capacity to serve as delivery vehicles for small-molecule STING agonists. Furthermore, the superior characteristics of polymer nanomaterials can enable their utilization as a novel STING agonist to stimulate anti-tumor immunity. In this review, the molecular mechanisms of cGAS-STING pathway activation are discussed. The recent development of small-molecules STING agonists is described. Then polymer nanomaterials are discussed as carriers for STING agonists in cancer immunotherapy, including polymersomes, polymer micelles, polymer capsules, and polymer nanogels. Additionally, polymer nanomaterials are identified as a novel class of STING agonists for efficient cancer immunotherapy, encompassing both polymer materials and polymer-STING agonists conjugates. The review also presents the combination of polymer-based cGAS-STING immunotherapy with chemotherapy, radiotherapy, phototherapy (both photodynamic and photothermal), chemodynamic therapy, and other therapeutic strategies. Furthermore, the discussion highlights recent advancements targeting the cGAS-STING pathway in clinically approved polymer nanomaterials and corresponding potent innovations. Finally, the potential challenges and perspectives of polymer nanomaterials for activating cGAS-STING pathway are outlined, emphasizing the critical scientific issue and hoping to offer guidance for their clinical translation.