STINGing Cancer: Development, Clinical Application, and Targeted Delivery of STING Agonists.

As cancer incidence continues to rise and conventional therapies remain of limited effectiveness, the search for novel and innovative cancer treatments is ongoing. In recent years, immunotherapies, including checkpoint inhibitors and cell-based approaches such as CAR-T cell therapy, have revolutionized the treatment of cancer. However, response rates even to well-established immunotherapies remain low in several types of cancer. Therefore, various novel immunomodulatory substances are currently under investigation, among them agonists of the intracellular signaling protein STING (STimulator of INterferon Genes). Activation of the STING signaling pathway can alter the cytokine profile within the tumor microenvironment (TME) and reshape the function of various immune cells. STING agonists have yielded promising results in preclinical studies, but this success has not yet been replicated in clinical trials. Consequently, STING agonists are optimized for greater potency and combined with nanotechnologies to enhance biodistribution and achieve sustained accumulation within the TME. This review summarizes a selection of STING agonists evaluated in clinical trials to date and discusses their effects on tumor-infiltration immune cells, especially macrophages. It highlights emerging candidates currently under investigation in preclinical studies, and explores nanotechnological approaches for their combinational use to enhance therapeutic efficacy.