Unlocking the potential of dCas9: Epigenetic targeting in cancer immunotherapy

Abstract

Cancer's profound medical challenge underscores the urgency for innovative solutions. Contemporary immunotherapy has formidable challenges dealing with immune evasion, complex tumor microenvironments (TME), and checkpoint inhibitors. Improvements to immunotherapy have been made through genome editing for which the Cas9 system is utilized, but its reliance on DNA repair mechanisms coupled with elevated off-target effects presents limitations. One alternative approach to gene editing is the modulation of gene expression using dCas9 and associated effectors. An advantage is dCas9's non-cleaving nature which reduces the chance of off-target effects and avoids permanent changes to the genome, offering enhanced safety as a gene modulation tool. We reviewed ongoing studies and clinical trials on immunotherapy, gene expression, and dCas9 to address whether gene modulation via dCas9 could be a viable solution to improve gene therapy. In (one/a few) studies found that dCas9's adoption decreases off-target effects, heightening its appeal for improving immunotherapy compared to traditional gene editing with Cas9. Therefore, integrating dCas9 in suppressing key target genes, dcas9 with effector domains or epigenetic modifiers could prove as a pivotal strategy, enabling precise gene regulation and epigenetic modification. Specifically, transcriptional activators like VP64 and repressors like KRAB exhibit the potential to modulate target genes when used with dcas9. Acknowledging limitations, such as mutations affecting gene regulation, this study underscores the transformative potential of dCas9-mediated epigenetic regulation in reshaping the landscape of cancer treatment and calls for further investigation to unlock its full therapeutic potential.