CRISPR-dCas9 epigenetic reprogramming in cancer: platforms, immuno-modulation and delivery challenges

CRISPR-dCas9 (catalytically dead Cas9) has revolutionized targeted epigenetic editing, offering locus-specific modulation of gene expression without altering DNA sequence. Beyond conventional approaches, novel strategies are rapidly emerging. These include combinatorial epigenetic reprogramming (co-recruiting multiple chromatin modifiers to a single locus), precision enhancer targeting (modulating oncogenic cis-regulatory elements), epigenetic modulation of immune pathways (reprogramming tumor or immune cells to boost anti-tumor immunity), and next-generation delivery systems for dCas9-based tools. This review synthesizes peer-reviewed literature (2015-2025) to highlight promising, yet still preclinical, advances in combinatorial reprogramming, enhancer targeting, immune-modulatory epigenetic approaches and delivery strategies, and to identify gaps that must be addressed prior to clinical translation. We highlight multi-effectors platforms (e.g. SunTag-like arrays, SSSavi modular docking, CRISPRoff memory writers) that amplify and diversify chromatin modifications. Precision enhancer editing systems (e.g. enCRISPRa/enCRISPRi) enable direct activation or silencing of distal regulatory elements in cancer cells. Epigenetic immunotherapy approaches use dCas9-activators to upregulate NK/T-cell ligands (MICA/MICB) and antigen-presentation genes (MHC I/II) in tumor cells. Finally, we survey innovations in dCas9 delivery that address in vivo challenges. Our review critically evaluates these advances, identifies gaps (off-target effects, context-dependence), and outlines future directions toward precision epigenetic therapies for diverse cancers.