Yi Qiao,1,* Lingyu Wei,2,* Yinjie Su,1 Qinyuan Tan,3 Xuecheng Yang,1 Shengxian Li1 

1Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, People’s Republic of China; 3Department of Urology, The People’s Hospital of Jimo, Qingdao, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xuecheng Yang, Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China, Tel +86-18661805062, Email m18661805062@163.com Shengxian Li, Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China, +86-18661808767, Email lishengxian@qdu.edu.cn

Abstract: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in triggering innate and adaptive immune responses through type I interferon activation and immune cell recruitment, holding significant promise for cancer therapy. While STING activators targeting this pathway have been developed, their clinical application is hindered by challenges such as poor membrane permeability, rapid degradation, suboptimal pharmacokinetics, off-target biodistribution, and toxicity. Nanoparticle-based delivery systems offer a promising solution by enhancing the stability, circulation time, tumor accumulation, and intracellular release of STING activators. Furthermore, combining nanoparticle-delivered STING activators with radiotherapy, chemotherapy, phototherapy, and other immunotherapies enables synergistic antitumor effects through multimodal mechanisms, addressing resistance to monotherapies and reducing risks of recurrence and metastasis. This review outlines the immunomodulatory mechanisms of the cGAS-STING pathway, surveys current STING-targeted activators, and comprehensively discusses recent advances in nanoparticle-mediated delivery strategies for STING activation. Additionally, we explore combinatorial approaches that integrate STING-targeted nanotherapies with conventional and emerging treatments. Finally, we highlight the current status, prospects, and challenges of nanoparticle-based STING activation for cancer immunotherapy.

Keywords: cGAS-STING, nanoparticle, immunotherapy, cancer, drug delivery