Nanoparticle‐Mediated STING Activation for Cancer Immunotherapy

Abstract

As the first line of host defense against pathogenic infections, innate immunity plays a key role in antitumor immunotherapy. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) pathway has attracted much attention because of the secretion of various proinflammatory cytokines and chemokines. Many STING agonists have been identified and applied into preclinical or clinical trials for cancer immunotherapy. However, the fast excretion, low bioavailability, nonspecificity, and adverse effects of the small molecule STING agonists limit their therapeutic efficacy and in vivo application. Nanodelivery systems with appropriate size, charge, and surface modification are capable of addressing these dilemmas. In this review, the mechanism of the cGAS-STING pathway is discussed and the STING agonists, focusing on nanoparticle-mediated STING therapy and combined therapy for cancers, are summarized. Finally, the future direction and challenges of nano-STING therapy are expounded, emphasizing the pivotal scientific problems and technical bottlenecks and hoping to provide general guidance for its clinical application.

Multifunctional Nanoassembly for MRI-Trackable Dendritic Cell Dependent and Independent Photoimmunotherapy

“…Moreover, FMMC­(+) treatment could directly activate the classic STING/pIRF3/IRF3/IFN-β pathway in tumor cells, promoting an antitumor immune response (Figure d). It is worth noting that although Mn 2+ is a STING activator, the selected concentrations of free or nanoscale Mn 2+ were insufficient to activate the STING/MHC-I signaling (Figures d and S11c, Supporting Information). ,− Furthermore, we conducted a T cell killing using FMMC­(+) pretreated 4T1 tumor cells to investigate whether the PDT-triggered up-regulation of MHC-I could directly activate CTLs to kill tumor cells independently of DCs. The results showed that treatment with FMMC­(+) significantly enhanced T-cell-mediated cancer cell death compared to treatment with FMMC alone (Figure f).…”

“…9−11 To tackle this predicament, several strategies have previously been developed to reinstate the activity of STING signaling function in STING-defective tumor cells, dendritic cells (DCs), and macrophages, thereby activating the subsequent T-cell-induced antitumor immune response both quantitatively and qualitatively. 12 cytosol DNA from tumor cells to APCs and subsequently activated robust STING pathway within APCs, thus promoting cancer immunotherapy against murine breast tumors. 13 Zhang et al exploited the iRGD-modified mesoporous silica nanoparticles loaded with DOX to recover the expression of STING and IFNβ proteins in tumor tissues, thereby enhancing the efficacy of chemo-immunotherapy against murine orthotopic glioma.…”

“…Eliciting the intracorporal immune system to eradicate the primary tumor and metastasis is rapidly emerging as a promising alternative modality for antineoplastic therapy, which has successfully transitioned from second-line to first-line treatment for certain types of cancers, such as breast carcinoma, lung carcinoma, and melanoma. − However, cancer cells and tumor microenvironment (TME) programmed by cancer cells enables immune evasion through various mechanisms, resulting in a low response rate to immunotherapy. − Cancer cells and antigen-presenting cells (APCs) can actively silence their own STING signaling to inhibit the canonical transcription of the type I IFN gene through the STING-IRF3-pIRF3-IFN-β pathway, which impairs antitumor immunogenicity and immune surveillance. − To tackle this predicament, several strategies have previously been developed to reinstate the activity of STING signaling function in STING-defective tumor cells, dendritic cells (DCs), and macrophages, thereby activating the subsequent T-cell-induced antitumor immune response both quantitatively and qualitatively. − Yu et al have recently reported a nanoformulation based on polymer (PLG- g -mPEG)-SN38 conjugate that induced the transfer of tumor cytosol DNA from tumor cells to APCs and subsequently activated robust STING pathway within APCs, thus promoting cancer immunotherapy against murine breast tumors . Zhang et al exploited the iRGD-modified mesoporous silica nanoparticles loaded with DOX to recover the expression of STING and IFNβ proteins in tumor tissues, thereby enhancing the efficacy of chemo-immunotherapy against murine orthotopic glioma .…”

Cancer vaccines in the clinic

“…However, their instability, poor membrane permeability, and toxicity have precluded their effective use as systemic agents. Novel delivery carriers and complexes may be able to overcome this challenge in the future 112–115 …”

“…Novel delivery carriers and complexes may be able to overcome this challenge in the future. [112][113][114][115] 6.4 | Advances in cell-based vaccination APC vaccines offer an alternative way to control immune-activating signals. While the ability to prime cells ex vivo with antigens and maturation stimuli is an attractive feature, these vaccines have multiple limitations.…”