Targeting intracellular mRNA m⁶A-modifiers in advancing immunotherapeutics

An impressive clinical success has been achieved in the treatment of various cancers employing immunotherapy and checkpoint blockade antibodies. However, limited therapeutic response has been observed in most of the patients receiving anti-PD1 antibodies remains a critical challenge, underscoring the need for innovative strategies to enhance immunotherapeutic efficacy to overcome these barriers. Several epigenetic drugs targeting DNA and histone proteins have received FDA approval are in the market. However epigenetic drugs targeting mRNA-modification machineries are still in infancy. The discovery of RNA modification enzymes (writers, erasers, and readers) has refuelled the scientific horizons in overcoming the challenges mainly associated with other pharmaceutical drugs. RNA modification especially 'm⁶A' is one of the well-studied epitranscriptomic mechanisms involved in regulating diverse biological processes via mRNA metabolism. To date more than 170 different types of RNA-modifications have been identified covering the different aspects of cellular, immunological, and biological functions. In this review we aim to summarize the potential of utilizing m⁶A-modifiers in discovering novel therapeutic procedure targeting immune cell subsets. Moreover, we have highlighted the possibilities of improving personalized therapy co-targeting m⁶A-modifiers engineered with other intracellular checkpoint genes like CISH. Furthermore, we have proposed dual therapeutic approach combining m⁶A-modifiers with anti-PD1 antibodies to enhance the efficacy of targeted medicines. Additionally, we have mentioned few biopharmaceutical companies and cell therapy clinics developing m⁶A-based RNA-modifying drugs (RMDs) and associated clinical trials. Our study will advance foundational knowledge in nurturing the potential of 'RNA epigenetic modifiers' in discovering novel therapeutic drug candidates, enhancing personalized therapy through immune cell engineering.