Advances in nanoplatform-based multimodal combination therapy activating STING pathway for enhanced anti-tumor immunotherapy

Abstract

Activation of the cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes (STING) has great potential to promote antitumor immunity. As a major effector of the cell to sense and respond to the aberrant presence of cytoplasmic double-stranded DNA (dsDNA), inducing the expression and secretion of type I interferons (IFN) and STING, cGAS-STING signaling pathway establishes an effective natural immune response, which is one of the fundamental mechanisms of host defense in organisms. In addition to the release of heterologous DNA due to pathogen invasion and replication, mitochondrial damage and massive cell death can also cause abnormal leakage of the body's own dsDNA, which is then recognized by the DNA receptor cGAS and activates the cGAS-STING signaling pathway. However, small molecule STING agonists suffer from rapid excretion, low bioavailability, non-specificity and adverse effects, which limits their therapeutic efficacy and in vivo application. Various types of nano-delivery systems, on the other hand, make use of the different unique structures and surface modifications of nanoparticles to circumvent the defects of small molecule STING agonists such as fast metabolism and low bioavailability. Also, the nanoparticles are precisely directed to the focal site, with their own appropriate particle size combined with the characteristics of passive or active targeting. Herein, combined with the cGAS-STING pathway to activate the immune system and kill tumor tissues directly or indirectly, which help maximize the use of the functions of chemotherapy, photothermal therapy(PTT), chemodynamic therapy(CDT), and radiotherapy(RT). In this review, we will discuss the mechanism of action of the cGAS-STING pathway and introduce nanoparticle-mediated tumor combination therapy based on the STING pathway. Collectively, the effective multimodal nanoplatform, which can activate cGAS-STING pathway for enhanced anti-tumor immunotherapy, has promising avenue clinical applications for cancer treatment.