Exploiting RIG-I-like receptor pathway for cancer immunotherapy

Abstract

RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize “immune-cold” tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.

Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy

“…In addition to the four aforementioned ligands, retinoic acid-inducible gene I (RIG-I), which is a member of the (RIG-I)-like receptor family, has also been reported to interact directly with Tim-3. Specifically, Tim-3 inhibits RIG-I expression in macrophages through the action of STAT1, promotes RIG-I ubiquitination and degradation through the action of the E3 ligase RNF-122, and subsequently inhibits type I interferon (IFN) production and antiviral activity [48][49][50]. The first anti-TIM-3 mAb, sabatolimab, was developed for use in solid tumor therapy, and it works by blocking the binding of TIM-3 to its ligands Gal-9 and PtdSer.…”

Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas

“…Moreover, there is a growing preference for dual-functional siRNAs designed to activate RIG-I, such as 5’-ppp siRNAs designed for cancer therapy. These siRNAs suppress cancer genes or drug-resistant genes while activating RIG-I-mediated immune responses, providing therapeutic advantages in treating viral infections and various diseases, including cancer [ 18 , 19 ]. Combining gene knockout with RIG-I activation represents a promising approach for anticancer therapy.…”

“…While the activation of innate immunity by dsRNA is not universally desirable, it can prove beneficial in specific scenarios such as viral infections and cancer treatment [ 18 ]. In recent years, researchers have developed bifunctional 5’-ppp siRNAs capable of simultaneously activating RIG-I-mediated immune responses and inhibiting the expression of oncogenes or drug-resistant genes [ 19 ].…”

UiO-66 nanoparticles combat influenza A virus in mice by activating the RIG-I-like receptor signaling pathway

“…The copy number of viral HA gene and expression of nucleoprotein were also significantly increased. This indicates that the protective effect of UiO-66 NPs against IAV infection was dependent on the presence of RIG-I, which is a key receptor involved in viral infection [ 52 ]. In addition, RIG-I directly inhibits viral replication independent of antiviral signaling [ 53 ].…”