The Innate Immune Signalling Pathways: Turning RIG-I Sensor Activation against Cancer

SIMPLE SUMMARY: The clinical success in immunotherapy has been remarkable, and, at the same time, disappointing. The immune context of the tumour microenvironment has an influence on tumour initiation, response, and therapy. It is an urgent matter to explore mechanisms shaping the tumour microenvironment for further progression of immunotherapy. The immunoreceptor retinoic acid-induced gene-I (RIG-I) has emerged as a promising target molecule to activate adoptive immunity via activation of innate immunity. In this paper, we highlight basic mechanisms of RIG-I signalling in the tumour microenvironment, broadening to the most recent preclinical studies that employ RIG-I agonists. We also present an up-to-date selection of clinical trials designed to prove the antitumour role of RIG I, and that may result in improved therapeutic outcomes for cancer patients. ABSTRACT: Over the last 15 years, the ability to harness a patient’s own immune system has led to significant progress in cancer therapy. For instance, immunotherapeutic strategies, including checkpoint inhibitors or adoptive cell therapy using chimeric antigen receptor T-cell (CAR-T), are specifically aimed at enhancing adaptive anti-tumour immunity. Several research groups demonstrated that adaptive anti-tumour immunity is highly sustained by innate immune responses. Host innate immunity provides the first line of defence and mediates recognition of danger signals through pattern recognition receptors (PRRs), such as cytosolic sensors of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMP) signals. The retinoic acid-inducible gene I (RIG-I) is a cytosolic RNA helicase, which detects viral double-strand RNA and, once activated, triggers signalling pathways, converging on the production of type I interferons, proinflammatory cytokines, and programmed cell death. Approaches aimed at activating RIG-I within cancers are being explored as novel therapeutic treatments to generate an inflammatory tumour microenvironment and to facilitate cytotoxic T-cell cross-priming and infiltration. Here, we provide an overview of studies regarding the role of RIG-I signalling in the tumour microenvironment, and the most recent preclinical studies that employ RIG-I agonists. Lastly, we present a selection of clinical trials designed to prove the antitumour role of RIG I and that may result in improved therapeutic outcomes for cancer patients.